bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of immunotherapy (I-O)-associated immune cell (IC) dynamics and PD-L1 expression using multispectral immunohistochemistry (mIHC) and single-cell hierarchical regression modeling in early-stage breast cancer (ESBC).
Authors: Sanchez Katherine , Martel Maritza , Chang Shu-Ching , Wu Yaping , Sun Zhaoyu , Nyberg Richard , Redmond William L , Pucilowska Joanna , Aliabadi-Wahle Shaghayegh , Imatani James , Conlin Alison Katherine , Bernard Brady , Shah Monil , Wadell Dottie , Laxague Deborah R. , Wen Lu , Li Qiao , Wolf Gregory T. , Urba Walter John , Page David B. 
Published: May 2019

e12070 Background: In triple negative breast cancer (TNBC), anti-PD-L1 is associated with gains in overall survival, however only in tumors with > 1% PD-L1+ ICs. Locoregional cytokine therapy is being evaluated as a method of priming and redirecting ICs to tumors, which may increase I-O benefit particularly in PD-L1 negative tumors. We report a sensitive method of quantifying I-O-related changes in PD-L1 and ICs using mIHC and single-cell hierarchical regression, which controls for within-tumor and across-patient PD-L1/IC heterogeneity. Methods: Pre-treatment and resection tissues from a phase Ib trial of locoregional cytokines (IRX-2, n = 16 subjects) in ESBC were analyzed. IRX-2 contains immunostimulatory cytokines (GM-CSF, IL-2, IFN-α, INF-γ, and IL-12) and was injected in peri-areolar tissue, which communicates directly with tumor-draining lymphatics. Specimens were analyzed for 1) H&E stromal TILs score; 2) clinical PD-L1 IC expression (Ventana SP142, 2 blinded pathologists); and 3) mIHC (PerkinElmer Vectra). InForm software was used to obtain geospatial outputs of tumor cells (CK+) and ICs (CD3, CD8, CD163) across multiple regions of interest (mean:18; range: 9-32). Mixed-effects modeling was used to evaluate for changes in PD-L1, ICs, and IC/tumor distance metrics. Results: PD-L1 and IC quantity by mIHC was highly concordant with clinical PD-L1 IC classification (JT test = 211, p < .001) and TIL score (r = 0.77). Cytokine therapy was associated with higher PD-L1 IC classification in 9/13 tumors, and increased PD-L1 ICs by mIHC in 14/15 (+337%, 95% CI: 120,769%). After adjusting for heterogeneity, cytokine therapy increased CD3+CD8+ ICs (+173%, CI: 93,287%) and CD3+CD8- ICs (+120%, CI: 21,301%). Therapy was also associated with increased effector-helper T-cell clustering (nearest-neighbor distance, -40%, CI: -29,-50%) and effector cell tumor localization (stromal-tumor interface CD8+ density +90%, Cl: 74, 305%). Conclusions: Our method is concordant with clinical PD-L1 and sTILs scores, and can additionally quantify IC and IC distances. This assay may allow for comparative I-O assessments with increased resolution, and will be used in a randomized phase II trial of pembrolizumab, chemo +/- IRX-2 in stage II/III TNBC.
Predicting response to neoadjuvant chemotherapy in nonmetastatic hormone receptor-positive breast cancer using 21-gene Breast Recurrence Score test.
Authors: Thekkekara Romy Jose , Bharadwaj Sushma , Yadav Udit , Baranwal Anmol , Peace David , Rogowski Wendy , Sekosan Marin , Lad Thomas E. , Marcus Elizabeth A. , Ferrer Karen , Shah Mousami , McDunn Susan H. 
Published: May 2019

e12093 Background: The Recurrence Score (RS) result based on the 21-gene Oncotype DX Breast Recurrence Score assay is standard of care in deciding adjuvant chemo-hormonal therapy versus hormone therapy alone in hormone-receptor positive (HR+), HER 2 negative, node–negative breast cancer. This study explores the role of RS result in predicting the response to neoadjuvant chemotherapy (NACT). Methods: In this retrospective single institution cohort study, electronic medical records of 148 women with HR+, HER 2 negative, non-metastatic breast cancer who received NACT from 2006 onward were screened. 38 patients were excluded due to lack of tissue for testing. Pretreatment biopsy blocks were sent to Genomic Health, Inc. for Oncotype Dx testing. Low RS result was defined as ≤25. Pathologic complete response (pCR) was defined as no residual tumor. Partial response (PR) was residual tumor with > 25% decrease in the largest dimension. No response (NR) was defined as < 25% decrease in the tumor post NACT. Progression (PD) was defined as increase in size of original tumor or new site(s) of disease. Results: Of the 110 patients studied, 58% were postmenopausal women. Fifty percent were African American, 12% were Caucasian and 27% were Hispanic. Invasive ductal carcinoma was the predominant histology (86%). Most patients had > T2 disease (97%) with 73% being clinically node positive. Adriamycin based NACT regimen was used in treating 86.3% of the women. Forty patients (36.4%) had tumor with RS≤25. NR/PD was significantly higher in tumors with RS≤25 (27/40) vs RS > 25 (13/70) (OR: 9.1, 95% CI: 3.7-22.2, P< 0.001). pCR was seen in 16% with RS > 25 and 0% with RS ≤25. Response to NACT (pCR/PR) was 32.5% in RS≤25 vs 81.4% in RS > 25. In tumors with response, RS > 25 was associated with a greater percent decrease in the tumor size compared to RS≤25 (median decrease of 71% vs 52%, P= 0.033). Conclusions: HR+, HER 2 negative, RS≤25 breast cancer is associated with increased rates of NR/PD and is unlikely to respond to NACT. Recurrence Score result determination in pretreatment breast cancer biopsy samples can be an effective tool to select patients with non-metastatic breast cancer for NACT. Studies are needed to determine novel neoadjuvant therapeutic approaches in patients who are candidates for neoadjuvant therapy but are unlikely to benefit from NACT.
Biomarkers involved in the neoadjuvant therapy response in triple-negative and Her2+ subtypes breast cancer.
Authors: Bofill Salvador , Benavent Marta , Gil Ana , Pineda Antonia , Molina-Pinelo Sonia , Gonzalez Rosario , Montaño Alvaro , Ruiz Borrego Manuel , Falcon Alejandro , Garrigos Carmen 
Published: May 2019

e12098 Background: Neoadjuvant systemic therapy for breast cancer is used increasingly for patients with breast cancer. One of the more compelling theoretical arguments for primary systemic therapy is its value as an in vivo test for drug sensitivity. The oncogenesis of breast cancer, progression and development of metastasis is influenced by the deregulation of a multitude of processes. Several long non-coding RNAs (LncRNAs) and genes are important regulators of gene expression, acting at almost all regulatory levels: transcriptional, posttranscriptional, epigenetic, and protein translation. Our main objective was to identify the differential expression of genes and LncRNAs in paraffin-embedded breast cancer samples Her2+ and triple negative (TN) subtypes in responders (R) and non-responders (NR) patients (pts) to neoadjuvant therapy. Methods: The expression RNAs was analyzed by ClariomD Asssay (ThermoFisher). Results were analyzed with Transcriptome Analysis Console and with in-house scripts in R (version 3.5.1). Data were corrected and normalized using Robust Multichip Average method from the oligo package. Expression was summarized at gene level using the corresponding annotation for ClariomD array BrainArray. Expression analyses were performed with limma package. We defined R (RCB 0; n = 29) and NR (RCB III; n = 11) pts. Results: The differential expression (p < 0.01) of two LncRNAs (RP1-213J1P_B.1 and AC053503.12), one miscellaneous RNA (miscRNA) (Metazoa_SRP) and five genes (STMND1, C8orf33, RP11-144G6.12, ZNF555, RGS2) were found between R and NR. Among others, we highlighted one of these LncRNAs (AC053503.12) and one gene (Metazoa_SRP) that were also identified in TN R (n = 11) vs NR (n = 6). In the Her2+subtype, STMND1 gene also showed a differential expression in R (n = 18) vs NR (n = 5). Conclusions: We found these LncRNAs, miscRNA and genes were involved in different cancer pathways and the their differential expression in R vs NR pts suggest that they could be involved in the response to neoadjuvant therapy in TN and Her2+ subtypes breast cancer. LncRNAs, miscRNA and genes differentially expressed are being independently analyzed by individual qPCR assays in the study cohort.
Association of pathologic non-complete response of axillary node with outcome after neoadjuvant chemotherapy in node positive breast cancer.
Authors: Chen Shin-Cheh , Chang Hsien-Kun , Lin Yung-Chang , Lin Yung-Chang , Shen Shih-Che , Kuo Wen-Lin , Yu Chi-Chang , Chou Hsu-Huan , Chu Chia-Hui , Huang Yi-Ting , Ueng Shir-Hwa 
Published: May 2019

e12101 Background: The pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) correlates with better outcome in specific subtype of breast cancer and the axillary nodal pCR (N-pCR) rate are more common than breast pCR (B-pCR). While only a few studies to compare the survival in terms of B-pCR and N-pCR, and no study compare between the outcome for those non pCR either in breast or axillary node. Methods: A cohort of 968 cytologically proved nodal metastatic breast cancer (cT1~4N1~2) received NAC in a single medical center between 2005~2017 were analyzed retrospectively. NAC regimen included anthracycline and taxanes in all patients, Trastuzumab was used in 308(70.3%) HER2(+) patients. The percentage of both breast and axillary pCR (T-pCR) 、B-pCR and N-pCR were compared in different subtypes. The impact of T-pCR、B-pCR and N-pCR to DFS and OS were analyzed using univariate and multivariate Cox proportional hazard model. Results: The median follow-up time was 45 months. The median age was 49 years old, average tumor size was 4.2cm, and 543 (56.1%) patients were N1 disease. 382(39.5%) patients were HR(+) HER2(-), 222(22.9%)were HR(+)HER2(+),216(22.3%) were HR(-)HER2(+) and 148(15.3%) were HR(-)HER2(-). After NAC, T-pCR was found in 213 (22.0%) patients, B-pCR and N non-pCR in 31 patients, N-pCR and B non-pCR in 245 patients and T non-pCR in 479 patients. N-pCR rate(47.3%) were significantly higher than B-pCR(25.2%) and this trend found in all subtypes ( P<0.0001).The predicting factors of N-pCR were N1,HER2(+) and HR(-). In survival analysis the pCR (either T,B or N) patients had significantly better 5-year DFS and OS than non- pCR(T-pCR v.s T non-pCR, DFS,85.1% v.s 58.4%;OS,91.2% v.s 73.6%,p<0.0001). B-non pCR had a significant better DFS than T non Pcr(65.1% v.s 58.4%,p=0.041) and non- significant. Cox better 5-year OS(78.9% v.s73.6%,p=0.059). Cox regression model demonstrated that T4,N2,grade 3, HR(-) and T non-pCR were poor prognostic factors in DFS and OS. Conclusions: The study demonstrated higher N-pCR rates than B-pCR in all subtypes after NAC, either T-pCR;B-pCR or N-pCR were associated with better outcome than non pCR. The worst outcome found in those T non-pCR or N non-pCR.
HER2 cluster amplification as a factor of an especial sensitivity for anti-HER2 neoadjuvant therapy with biosimilar of trastuzumab in Russian women with breast cancer stage II-III.
Authors: Kolyadina Irina Vladimirovna , Gordeeva Olga , Ganshina Inna , Zavalishina Larisa , Andreeva Yulia , Frank Georgy , Savelov Nikita , Tuzova Elena , Zhukova Lyudmila , Vishnevskaya Yana , Arkhipov Aleksandr , Bokhian Vahan Yurikovich , Komov Dmitry , Poddubnaya Irina 
Published: May 2019

e12102 Background: Effect of neoadjuvant chemotherapy (NACT) is extremely important for patients with HER2-positive breast cancer stage II-III as it correlates with long-term outcomes. However, predictive factors for achieving complete pathologic response (pCR) remain unclear. Aim of the study: Assess an impact of clinical, morphological and genetic factors on pCR achievement in patients with HER2-positive breast cancer stage II-III treated by biosimilar of trastuzumab. Methods: We studied treatment results in 73 patients with HER2-positive breast cancer (BC) stage II-III (aged 29-71, median – 51 years), treated with NACT with anti-HER2 therapy and radical surgery in “N.N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation in 2015-2018. After radical surgery pathologic response was assessed. Initially operable tumors were observed in 45,2% patients, locally advanced - in 53,4%. Luminal HER2-positive BC was diagnosed in 41,1%, non-luminal HER2-positive in 58,9%. Ki67 was high (≥ 20%) in 91,5%. NACT included anthracycline and non-antracycline regimens with addition of biosimilar of trastuzumab ± pertuzumab. Radical mastectomy was performed in 78,8% patients, 21,2% had breast-conserving surgery. We studied biopsies obtained before the start of treatment in all women, HER2 amplification was detected by HER2 IQFISH pharmDx (DAKO) kit in accordance with ASCO/CAP 2018 guidelines. In 87,1% HER2+ status was defined as ASCO/CAP 2018 category 1; cluster amplification was detected in 30,1% patients. We analyzed the rate of bpCR и tpCR achievement depending on clinical, pathological data and amplification of HER2. Results: Pathologic complete response in primary tumor (bpCR) was achieved in 57,4%, both in primary tumor and lymph nodes (tpCR) – in 48,9% patients; bpCR achievement depended on age, NACT regimen, addition of pertuzumab and HER2 copy number ( < 0,05). The highest rate of bpCR was noted in women aged 50 and older (71,9%, p = 0,026); in patients received TCH±Р regimen (80,0%, p = 0,045); with addition of pertuzumab (88,9%, p = 0,049); and if cluster amplification was detected (81%, p = 0,013). Cluster amplification was the only one significant predictive factor for achieving tpCR: with cluster amplification - 68,8%, without - 38,7% (p = 0,049). Conclusions: Cluster amplification of HER2 is the most significant factor of especial sensitivity for NACT with biosimilar of trastuzumab in HER2-positive BC stage II-III.
Retrospective single-center outcome analysis of neoadjuvant and palliative treatment with dual trastuzumab and pertuzumab in HER2-positive breast cancer.
Authors: Marhold Maximilian , Ionce Lea Roxana , Christ Alexandra , Aretin Marie-Bernadette , Sagaster Verena , Exner Ruth , Wimmer Kerstin , Devyatko Yelena , Fitzal Florian , Steger Guenther G. 
Published: May 2019

e12114 Background: Her2-positive (Her2pos) breast cancer (BCa) is the second most lethal subtype of BCa. The treatment of Her2-positive BCa was revolutionized due to the dual use of trastuzumab and pertuzumab (T+P) in recent years both in the neoadjuvant and the palliative setting. Although several years have passed after initial approval of these drugs, single-center outcome data as reported by clinicians is sparse. In this retrospective study, we set to assess outcomes measures at our institution, Austria’s largest academic hospital, for the use of T+P in early and metastasized BCa. Methods: We acquired records on combined pertuzumab and trastuzumab orders from our intramural drug order software (CATO, Cato Research, Durham, NC, USA) for the time period of May 2013 to March 2018. Further, using electronic patient histories, we described both the neoadjuvant and palliative patient groups by assessment of body weight/size, tumor stage, histology including immunohistochemistry (IHC), lines of oncological therapies received, ejection fraction (EF) drops>10%, deaths and most importantly the outcomes measures pathological complete response (pCR, neoadjuvant cohort) rate and progression-free survival (PFS, palliative cohort). Results: 120 breast cancer patients were given dual therapy with T+P. The neoadjuvant cohort contained 63 patients, while the palliative cohort included 57 patients. All patients included were female. Full histology including IHC data was available for 47 of 63 patients in the neoadjuvant cohort and 30 of 57 patients in the palliative cohort. BMI was 25.6 and 23.3, respectively, on average. The mean age was 54 years in the neoadjuvant and 56 years in the palliative cohort. 73.6% (39/53) and 65.9% (29/44) of tumors were ER positive as determined by IHC. While neoadjuvant patients obtained an average of 6.5 cycles, patients within the palliative cohort received a mean of 17.3 cycles of T+P. 0 and 17 deaths were observed in the respective cohorts. Data on pCR and PFS was available for 95.2% and 91.2% of patients, respectively. The pCR rate within the neoadjuvant cohort was 46.7% (28/60), and mean PFS across all treatment lines of the palliative cohort was 10.2 months. Conclusions: We report retrospective single-center outcome data for the combined use of trastuzumab and pertuzumab in both early and metastatic Her2pos BCa in line with previously published data.
Doxorubicin response prediction in neoadjuvant breast cancer therapy.
Authors: Buhl Anna Sofie Kappel , Christensen Ib Jarle , Knudsen Steen , Jensen Peter Buhl 
Published: May 2019

e12119 Background: Neoadjuvant treatment for breast cancer (BC) is an important remedy if the tumors are responding adequately. Still, there is no biomarker guidance resulting in many patients receiving chemotherapy with no efficient antitumor effect. We study a multigene mRNA-based technology for drug response prediction (DRP). DRP has been thoroughly validated in other settings, latest in prediction of epirubicin efficacy in advanced BC [1]. Here are the results of the DRP method in the prediction of response to neoadjuvant doxorubicin in early BC. Methods: The DRP correlates sensitivity of the applicable drug in cell lines with background mRNA. This is combined with gene expression patterns from >2.000 tumors of different origin to ensure clinically usefulness. The higher DRP score, the higher likelihood of response. Blinded predictions of doxorubicin DRP scores were compared to response data which originated from a phase II trial [2], where the study population received neoadjuvant doxorubicin and cyclophosphamide (N=279). The patients had histologically confirmed primary invasive breast adenocarcinoma (T2-3, N0-3, M0, tumor size ≥ 2.0 cm, ER+/- and HER2+/-). Statistical analysis was done using logistic regression. Results: Table shows the distribution of response and DRP scores, showing higher DRPs are correlated to better clinical outcome. This is demonstrated by logistic regression ( p=0.002), odds ratio for response 2.2 (95% CI:1.3-3.4). Multivariate analysis showed that the DRP was independent of other covariates. Conclusions: The DRP can predict which patients will be high likelihood responders to neoadjuvant doxorubicin. Modern multigene technologies may help assist clinicians in choosing between upfront surgery or neoadjuvant chemotherapy. Complete response (CR), Partial response (PR), Stable disease (SD), Progression of Disease (PD). 1. Buhl ASK, et al. (2018): Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study. Breast cancer research and treatment. doi: 10.1007/s10549-018-4918-4. 2. Horak CE et al. (2013): Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. Clinical cancer research. doi: 10.1158/1078-0432.ccr-12-1359.[Table: see text]
Biological behavior of HER2+ breast cancer: Differences based in hormone receptor expression.
Authors: Da Silva Maria Joao Ribeiro , Abreu Miguel Henriques , Azevedo Sergio Xavier , Alpoim Tiago , Sousa Susana , Pereira Deolinda 
Published: May 2019

e12120 Background: Breast carcinoma is a heterogeneous disease whose therapeutic approach idepends on the classification into molecular subtypes. Despite the impact the expression of hormone receptors (HR) among patients with overexpression of HER2 is already the target of some studies, there is a lack of analysis in the era of treatment with adjuvant trastuzumab. Methods: This stydy consists in a retrospective analysis of cases of tumors with overexpression of the HER2 receptor (HER2 +), and HR- treated at an oncological center, comparing their biological behavior with cases of HR +/ HER2 + tumors, thus controlling for classic prognosis. Results: We analised a total of 420 patients, of whom 210 with HR+/HER2+ tumors and 210 HR- / HER2 +, with median ages of 52 years and 53 years, respectively. They accounted for 89.5% of cases of stage I to III disease. The groups were balanced in clinical characteristics. There was a higher proportion of undifferentiated and inflammatory tumors in the RH-/ HER2 + group, and in this group higher rates of complete pathological responses to treatment were observed (50.8% vs. 30.0%, p < 0.001). During the follow-up 30 recurrences occurred, 18 in the HR- / HER2 + group, and 12 in the HR + / HER2 +. There was lower disease-free survival in the HR-/HER2 +, on average 69.1 months, compared to 74.3 months in the group HR+/HER2 + (p = 0.001). The first metastatic site involved visceral location in 13 cases (72.2%) in HR- / HER2 + tumors (CNS involved in 8 cases), and in 8 cases (66.6%) in HR + / HER2 + tumors (CNS in 1 case). There was an association between relapse and response to primary systemic treatment (p = 0.003), with no relation demonstrated with other clinicopathological characteristics. In the global sample, there were 28 deaths, corresponding to 17 in the HR-/HER2 +, and 11 in the HR+/HER2 + group. There were significant diferences in OS, showing worse prognosis of HR- disease (mean of 70.7 months vs. 106.6 months, p = 0.001). There was an association of mortality with the presentation as an inflammatory tumor and involvement of the CNS. Conclusions: This study supports the concept of two distinct entities according to the expression in HER2 + disease, justifying therapeutic approaches and eventually different follow-up strategies.
Combining denosumab (D) and trastuzumab (T) as a novel treatment strategy in HER2-positive (+) breast carcinomas (BC).
Authors: Karamouzis Michalis , Zoi Ilianna , Xingi Evangelia , Thomaidou Dimitra , Papavassiliou Athanasios G. 
Published: May 2019

e12506 Background: HER-2 is overexpressed in 20–30% of BC, indicating poor prognosis. RANKL/RANK pathway is implicated in HER-2(+) BC. The molecular mechanism and the potential of dual targeting have been evaluated and showed promising results. Methods: We used SKBR3, BT474, MCF7, MDA-MB-453 human BC cell lines. We examined the expression of RANK and RANKL using RT-PCR, Western-Blot and immunofluorescence. The interaction between RANK and HER-2 was detected using Proximity Ligation Assay (PLA) which enables the visualization of interacting proteins. NF-κB pathway activation was studied using Western-Blot. We used inhibitors of both pathways. Cell viability and cell migration was evaluated using XTT and scratch assay, respectively. Results: Cell lines differentially express RANK and RANKL. RANK receptor dimerizes with HER-2. RANK/ HER-2 dimer number depends on HER-2 expression (SKBR3: 5.4, BT474: 8.2, MCF7: 0.7, MDA-MB-453: 0.3). RANK/HER-2 dimers are decreased in the presence of the inhibitors D and T, while they are increased after RANKL (R) treatment in SKBR3 (m:5.4, D:1.2, T:1.9, DT:0.6, R:11.8,) and BT474 (m:8.2, D:3.1, T:4.3, DT:0.7, R:11.6). MCF7 and MDA-MB-453 do not correspond to inhibitors. The combination treatment of SKBR3 with the inhibitors further decreased NF-κB pathway activation compared to single targeting. SKBR3, after inhibitors treatment, also exhibit reduced cell proliferation (m:100%, D:84.7%, T:51.57%, DT:48.61%, R:111%) and lower metastatic potential (m:26.02%, D:33.56%, T:16.54%, DT:13.75%, R:32.36%) compared to mock cells (m) and increased values in RANKL presence. The combination treatment of SKBR3 with D and T has an advantage in functional proliferation assays compared to single targeting. Conclusions: The results indicate a direct association between HER-2 and RANKL/RANK pathway in HER-2(+) BC growth. We also present data suggesting that the combination of trastuzumab and denosumab may have therapeutic benefit in certain BC patients.