bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanosomal docetaxel lipid suspension (NDLS) based (neo) adjuvant chemotherapy improves pathological complete response (pCR) in patients with breast cancer.
Authors: Revathi Badiginchala , Dattatreya Palanki Satya , Suresh Attili Venkata Satya , Nirni Sharanabasappa Somanath , Andra Vindhya Vasini 
Published: June 2022

e12591 Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS versus conventional docetaxel-based neo/adjuvant chemotherapy in patients with breast cancer. Methods: Patients with stage IIb-III breast cancer were randomized (1:1) to receive neoadjuvant doxorubicin and cyclophosphamide (AC) followed by conventional docetaxel (arm A) or NDLS (Doceaqualip; arm B) at a dose 75 mg/m2 IV every 3-weekly for 4 cycles as neo/adjuvant therapy. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received treatment as per clinical practice. The study outcomes included pathologic and clinical response rates (pCR, CR), and overall survival (OS). Results: 60 patients were randomized to arm A (n=30) or arm B (n=30). The baseline characteristics were similar in both groups. The pathological and clinical response rates were comparable between the NDLS and conventional docetaxel arms (P>0.05) (Table). The efficacy outcomes were not affected by the receptor (estrogen, progesterone, and HER2) status. The pCR and CR rates were higher in patients who received neoadjuvant AC followed by neoadjuvant NDLS/T versus neoadjuvant AC followed by adjuvant NDLS/T. At a follow-up of 6 months, median OS was not evaluable in both arms as all patients were alive at follow-up post study completion. Grade 3/4 infusion-related reactions, hyperglycemia and neuropathy were noted in 5, 8 and 3 patients, respectively, in the conventional docetaxel arm while it was not reported in any patient in the NDLS arm. Conclusions: NDLS based neo/adjuvant chemotherapy was efficacious in the treatment of breast cancer and showed comparable pCR, CR and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.[Table: see text]
Multimodal approach to capture spatially resolved single-cell tumor heterogeneity in breast cancer.
Authors: Cook Daniel , Lopez Dorys , Antony Anu K. , Team The SimBioSys , Cole John A. 
Published: June 2022

e12597 Background: Tumor heterogeneity is known to play a key role in drug response and resistance. However, knowledge of tumor heterogeneity is largely limited to genetics and biopsy samples representing one region of the tumor. The study of spatial tumor heterogeneity is gaining more interest as researchers and clinicians realize that biopsies might miss biomarker information. Although several approaches like single-cell RNA seq and multiplex IHC/IF are used to study spatial heterogeneity, these methods tend to be costly and time consuming. Additionally, there is no consensus on how to interpret these results for optimizing therapy, making it harder to implement these approaches in the clinic. Methods: Here we present a state-of-the-art technique to characterize tumor heterogeneity within individual patient tumors by integrating single cell RNA-seq data with biophysical modeling, using SimBioSys’ TumorScope (TS) – a biophysical modeling platform. As a proof of concept, we compared intra-tumoral heterogeneity from experimental single cell RNA-seq studies from TNBC patients (n=8) to to simulated intra-tumoral heterogeneity within TNBC patients from the ISPY-1 trial (n = 10). We also compared simulated vs. experimentally measured bulk transcriptional profiles within individual patients. Results: We found that the correlation between individual single-cell transcriptomes to biopsy transcriptomes was low (median Spearman correlation ̃ 0.5). However, using TS to predict single-cell scale transcriptomics within a tumor based on biophysical characteristics of the tumor resulted in correlations of ̃ 0.86, between simulated and experimentally measured transcriptomes (range = 0.85 - 0.87). TS allowed the simulated single-cell RNA-seq data to create spatially resolved single-cell maps that quantify the spatial expression of key tumor biomarkers across the whole tumor including Ki67, HER2 and PDL1. The spatial distribution of these biomarkers can have important implications for therapy and patient prognosis. A more comprehensive understanding of the distribution of these molecular markers across the tumor could inform if some tumors deserved a different Ki67 score, if some patients are not receiving HER2-targeted therapy because of HER2 uneven expression across the tumor, and if PD-L1 could improve as a biomarker by considering its spatial expression. Conclusions: In summary, we present a novel approach to characterize spatial tumor heterogeneity directly from patient MRIs using the TS biophysical modeling platform. This technology is less time consuming and less costly than other approaches, making it accessible for use in hospitals at a larger scale.
Serum thymidine kinase 1 and its kinetics in HER2-positive breast cancer: Results from the Swedish phase II PREDIX HER2 trial.
Authors: Zhu Yajing , Wang Kang , Zerdes Ioannis , Matikas Alexios , Bergqvist Mattias , Elinder Ellinor , Bosch Ana , Lindman Henrik , Einbeigi Zakaria , Andersson Anne , Carlsson Lena , Dreifaldt Ann Charlotte , Isaksson-Friman Erika , Hellstrom Mats , Johansson Hemming , Bergh Jonas C. S. , Hatschek Thomas , Foukakis Theodoros 
Published: June 2022

e12598 Background: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in HER2-negative early and metastatic breast cancer (BC). Here we present the first report of TK1 in HER2-postitive BC. Methods: In the PREDIX HER2 trial, 202 patients with HER2-positive BC were randomized to 6 cycles of neoadjuvant trastuzumab, pertuzumab and docetaxel or trastuzumab emtansine every three weeks followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum was prospectively collected from all participants at multiple timepoints: At baseline, after cycles 2, 4 and 6, at end of adjuvant therapy and then annually for 5 years and in case of recurrence. TK1 activity was measured by DiviTum assay (Biovica, Sweden), blinded to treatment allocation, patient characteristics and outcome. TK1 activity was correlated with baseline characteristics, pathologic complete response (pCR) and event-free survival (EFS). Results: Baseline TK1 activity as categorical variable was not associated with tumor size or hormone receptor expression. An increase of TK1 activity was seen in the majority of cases after treatment (mean TK1 at baseline = 111.7, after cycle 2 = 1257.0, after cycle 4 = 1157.0, after cycle 6 = 1178.0). Neither baseline TK1, on-treatment TK1 nor its change from baseline to cycle 2 were significantly associated with pCR in multivariable logistic regression analysis (Table). Baseline TK1 activity was not predictive for differential benefit to the study treatments ( pinteraction = 0.19). After a median follow-up of 52.5 months, 21 patients had EFS events. There was no significant correlation between baseline TK1 activity and EFS in multivariable Cox regression analysis. Conclusions: Serum TK1 activity in HER2-positive BC increased following treatment with neoadjuvant therapy but was not correlated to pCR rates or EFS. [Table: see text]
Construction of a model for evaluating the efficacy of neoadjuvant chemotherapy for breast cancer and dynamic monitoring of ctDNA response to neoadjuvant chemotherapy.
Authors: Liu Zhaoyun , Yu Bo , Su Mu , Yuan Chenxi , Liu Cuicui , Yu Zhiyong , Yu Jinming 
Published: June 2022

e12600 Background: Neoadjuvant chemotherapy (NAC) is a routine treatment of choice for patients with locally advanced breast cancer. The pathological complete response (pCR) to NAC in breast cancer is closely related to a better prognosis. In addition, there have been few studies of the role of ctDNA in the dynamic monitoring of NAC, so we explored the prediction model of NAC to predict pCR and evaluated the role of ctDNA in the dynamic monitoring of NAC. Methods: A total of 269 breast cancer patients receiving NAC were enrolled, and a total of 266 tissue samples were collected. The tissue samples were sequenced using a panel covering 457 cancer-related genes to construct a pCR prediction model after NAC. A total of 267 blood samples were collected from 56 patients. Blood samples were collected at the indicated time points: before NAC (T0), after the first NAC and before cycle two (T1), during intermediate evaluation (T2), and after the end of NAC but before surgery (T3). We constructed a model to predict pCR after NAC by mutated genes and clinical factors, analyzed ctDNA of blood samples according to the mutated genes of the prediction model, and detected the dynamic monitoring role of ctDNA in NAC to predict prognosis. The median follow-up time for survival analysis was 898 days. Results: A total of 192 patients were enrolled to construct the prediction model. There were 51 patients in the additional validation set. We analysed the somatic mutations of 192 samples and constructed a predictive NAC response model including 5 SNV mutations (TP53, SETBP1, PIK3CA, NOTCH4 and MSH2), 4 CNV mutations (FOXP1-gain, EGFR-gain, IL7R-gain, and NFKB1A-gain), and 3 clinical factors (luminal A, Her2+ and Ki67). Analysing the ctDNA of 267 blood samples through a unique panel composed of 9 mutant genes in the prediction model, it was found that ctDNA positivity decreased with the passage of time during NAC, the ctDNA positive rates of ctDNA from T0, T1, T2 to T3 were 46%, 14%, 13% and 10%, respectively. According to survival data, pCR patients did not have disease progression after NAC. Among the non-pCR patients who had disease progression, the probability of non-pCR in patients with ctDNA cleared at T1, T2, and T3 was significantly lower than that in patients with uncleared ctDNA. Interestingly, patients who failed to achieve pCR but were ctDNA negative had a similar risk of metastasis and recurrence as those who achieved pCR. Finally, we found that the prediction model combined with ctDNA could predict pCR after NAC. It had high sensitivity and specificity and the AUC value reached 0.961. Conclusions: This study established a predictive model for predicting pCR after NAC. At the same time, ctDNA dynamic monitoring found that ctDNA status could predict NAC response and metastasis recurrence. Combining the prediction model and ctDNA status could better predict the NAC results.
Utility of interval imaging during neoadjuvant treatment of locoregional breast cancer.
Authors: Chacko Rebecca , Li Pin , Abdel-Razeq Nayef Hikmat , Godbole Manasi , Dabak Vrushali S. 
Published: June 2022

e12611 Background: National guidelines for breast cancer management do not recommend routine imaging during preoperative chemotherapy. Despite this, some clinicians use radiographic results as a surrogate marker of treatment response during the preoperative phase. In this retrospective investigation, we studied the correlation between neoadjuvant clinical decision making, midway imaging results and final pathologic responses. Methods: 394 patients with locoregional breast cancer who received neoadjuvant chemotherapy and definitive surgery within the Henry Ford Health System between 2015-2021 were included. Final pathologic response of patients who completed midway imaging were compared with patients who did not. The primary outcome was overall pathologic response rate. Results: Tumor histology and final pathologic response (PR) was compared in patients who received midway imaging (MI) to those who did not (Table). In the MI group, no statistically significant association between midway radiographic response and final PR was found (p = 0.078). Systemic treatment was changed in 14.7% of patients after MI, there was no association with treatment change and complete PR (p = 0.488), however none of patients who received a treatment change after MI had progressive disease on final PR, compared to 9.7% of patients who did not have a treatment change and had progressive disease on final PR (p = 0.035). Multivariate analyses showed no association between MI and complete PR, irrespective of the histological subtypes. 78.4% of patients had imaging at the end of systemic treatment, prior to surgery. Radiographic response on post-treatment imaging correlated with final PR (p < 0.001). Conclusions: This study did not detect an association between midway imaging during neoadjuvant therapy and a complete pathologic response in locoregional breast cancer, however a correlation was detected between post-treatment imaging response and final pathologic response. Changes to systemic treatment based on midway radiographic findings were not shown to improve the likelihood of complete pathologic response but may reduce risk of progressive disease. Based on this study, midway imaging should not be broadly ordered during preoperative treatment, unless there is concern for progressive disease, in which midway imaging may provide diagnostic benefit.[Table: see text]
The ratio of PD1+CD8+T cells in stromal area of tumor tissue is associated with the effect of neoadjuvant chemotherapy in HER2 negative breast cancer patients.
Authors: Gong Chang , Lin Qun , Cen Yinghuan , Fang Xiaolin , Shi Yu , Chen Letian , Luo Qing , Duan Zhuxi 
Published: June 2022

e12626 Background: For patients diagnosed with early breast cancer, surgery remains the standard of care. Early patients achieving pathological complete response (pCR) after neoadjuvant therapy have been proved to be associated with improved survival. However, the accurate prediction of pCR in a clinical setting remains challenging. Tumor infiltrating lymphocyte (TIL) levels have recently been identified as an independent predictor of pCR in breast cancer. However, due to extremely complex tumor microenvironment within tumor, the role of different immune cell subtypes in neoadjuvant chemotherapy (NAC) is inconclusive. This study aimed to explore the potentially predictive role and dynamic changes of immune cell subsets in patients with HER2 negative breast cancer receiving NAC. Methods: Since January 2020, tumor tissue samples of 12 HER2 negative breast cancer patients were collected at baseline and after NAC. Several kinds of immune cells including CD3+T cells, CD4+T cells, CD8+T cells, PD-1+CD8+T cells, Tregs, M1/M2 tumor associated macrophages(TAM), PD-L1+CD68+TAM, B cells, CD56bright NK cells and CD56dim NK cells in the tumor tissue were evaluated by multiple fluorescence immunohistochemistry (mIHC) and counted in intratumoral and stromal area for density and ratio. T test was used for the comparison of immune cells and statistical significance was set at p = 0.05. Results: We examined immune cell subtypes and PD-L1/PD-1 expression of 12 HER2 negative breast cancer patients. According to achieving pCR or not, these 12 patients were divided into two groups, pCR (n = 3) and non-pCR group (n = 9). The results showed that the ratio of PD1+CD8+T cells in stromal area of baseline tumor tissue of pCR group was significantly higher than non-pCR group (median ratio, pCR group vs. non-pCR group = 17.3% vs. 3.6%, p = 0.029).In addition, the ratio of PD1+CD8+T cells in stromal area of pCR group was still significantly higher than that of non pCR patients after NAC (median ratio, pCR group vs. non-pCR group = 20.7% vs. 2.6%, p = 0.0003). Conclusions: Whether at baseline or after NAC, the ratio of PD1+CD8+T cells in stromal area is associated with the effect of NAC in HER2 negative breast cancer.
Real-world PARPi treatment patterns and outcomes among patients with metastatic breast cancer.
Authors: Dawood Shaheenah S. , Brzozowski Kaylen 
Published: June 2022

e13005 Background: PARP inhibitors (PARPi) improves PFS among patients (pts) with HER2-ve metastatic breast cancer (MBC) and a BRCA1/2 mutation compared to physician choice of chemotherapy. The objective of this retrospective analysis was to look at the prognostic outcome associated with the use of PARPi therapy among pts with MBC in the real world setting. Methods: We utilized a federated network of de-identified health data representing approximately 84 million pt lives available through the TriNetX Research Network. We identified 767 pts with MBC treated with a PARPi. Overall survival (OS) was computed using the Kaplan Meier product limit method. Propensity score matching was performed on all comparisons of OS. Matching variables included age groups, prior platinum therapy, prior genitourinary malignancies, and secondary metastasis location. Results: Mean age was 56.3yrs. 718 pts had HER2- disease and 49pts had HER2+ disease. Median OS was 55.0m and 44.4m among pts with HER2- and HER2+ disease respectively. Median OS among was 58.3m and 48.6m among patients with HR+/HER2- and TNBC respectively(p = 0.18). Among pts with HR+/HER2- disease, 50.2% received PARPi in combination with endocrine therapy and 43.5% received CDK4/6i. Median OS among pts who received CDK4/6i + endocrine therapy prior to a PARPi and those that never received a CDK4/6i was 55.1m and 36.9m, respectively(p = 0.01). Among pts with TNBC, median OS among those that received PARPi prior to chemotherapy compared to those who received PARPi after chemotherapy was 52.5m and 47.6m respectively (p = 0.97). 169 HER2- pts had brain metastases. Median OS among pts who had brain metastases was 36.9m among pts with HR+/HER2- disease and 22.5m among pts with TNBC(p = 0.01). Among pts with no brain metastases, median OS was 60.6m among pts with HR+/HER2- disease and 56.3m among pts with TNBC(p = 0.91). Median OS among pts who were rechallenged with a PARPi compared to those who were not rechallenged with a PARPi was 58.3m vs 42m respectively (p = 0.05). Conclusions: To our knowledge this is the first data set to report activity of CDK4/6i among pts with HR+/HER2- MBC who received a PARPi, with an observed 18m OS advantage compared to pts who did not receive a CDK4/6i. In absence of brain metastases OS of pts with TNBC and HR+/HER2- is similar when treated with a PARPi.
The prognostic value of genetic alterations of gasdermin (GSDM) family genes in breast cancer.
Authors: Ding Zhenyu , Huang Tanxiao , Chen Juan , Gao Jinping , Yang Jiangjie , Liu Ming , Liu Yuanyuan , Chen Shifu , Piao Ying 
Published: June 2022

e13006 Background: Breast cancer (BC) is the most commonly diagnosed cancer in 2021, with an estimated 2.9 million new cases (31%) and the second leading cause of cancer death in women. Gasdermins are encoded by six paralogous genes: GSDMA, GSDMB, GSDMC, GSDMD, GSDME (also known as DFNA5) and DFNB59 (also known as pejvakin, PJVK). They play a key role in pyroptosis. Few studies addressing the association between genetic alterations in the GSDM family genes and breast cancer prognosis have been reported up to now. Methods: We used a public cancer research platform named cBioPortal to analyze a cohort of 1983 breast cancer samples. We defined overall survival (OS) as the time between the procedure date when the tumor specimen was collected and the date of death or last follow-up visit. We compared the survival curves of two groups using Kaplan-Meier method and log-rank tests. The statistical significance level was set to 5% (p < 0.05). Results: These genes were found in 685 (34.5%) samples with various genetic alterations, including missense mutation, splice mutation, truncating mutation, structural variant, amplification, deletion. GSDMC was the most frequently altered gene (18%), followed by GSDMD (17%), GSDMB (11%), GSDMA (10%), GSDME (2.5%), and PJVK (0.7%). Based on the result, patients were divided into the GSDM mutation and non-GSDM mutation group. The median OS of the GSDM mutation group was 124.57 months (Table), which is significantly shorter than the OS of the non-GSDM mutation group (log-rank test p = 5.64e-7). Conclusions: To our best knowledge, this analysis is the first investigation to evaluate the association between prognostic value and genetic alterations in GSDM family genes in breast cancer patients. Our investigation shows that genetic alterations in GSDM family genes can be used to predict poor prognosis in breast cancer patients. Further studies are warranted to verify and expand on these findings.[Table: see text]
The prognostic significance of disseminated tumor cells in bone marrow in patients with operable breast cancer: An updated analysis.
Authors: Dirix Luc Yves , Van Mileghem Laura , Prove Annemie , Vermeulen Peter B. 
Published: June 2022

e13013 Background: The main cause of death in breast cancer patients is the consequence of the spread and outgrowth of tumor cells at distant sites. The presence of disseminated tumor cells (DTCs) in the bone marrow at diagnosis is considered a predictor for metastasis. Methods: This is an updated analysis of a study in 102 patients with operable breast cancer on the significance of bone marrow micrometastases. The mean follow-up time is 127 months (range 10 - 142, median 129 months). Bone marrow aspirates were analysed for the presence of DTCs by a real time-polymerase chain reaction (RT-PCR) for cytokeratin 19 (CK) and mammaglobin (MAM).The aim of this study is to confirm the association between DTCs and disease-specific survival (DSS) as well as metastasis-free survival (MFS). Results: CK positivity was borderline significant for DSS (p = 0.054). MAM positivity was significantly prognostic for DSS with a hazard ratio (HR) of 3,110 (1,416-6,832) (p = 0,005). Patients positive for both CK and MAM did have a significant worse outcome with a HR for DSS of 7,329 (2,361 – 22,752) (p = 0,001). No significant influence on MFS was identified for CK (p = 0,658) or MAM positivity (p = 0,095). The combination of CK and MAM positivity did however confer a significantly increased risk for MFS (p = 0,043) at a HR of 4,126 (1,409-12,082). Conclusions: This study confirms the role of DTCs as a negative, prognostic factor in patients with operable breast cancer. The combination of CK and MAM is useful to identify this increased risk.