bluuebunny/crossref_metadata_2025_split huggingface dataset:
Involvement of NK cell molecular signatures in favorable prognosis of breast cancer patients.
Authors: Ascierto Maria Libera , Idowu Michael O , Zhao Yingdong , Bedognetti Davide , Ascierto Paolo Antonio , Bear Harry Douglas , Wang Ena , Marincola Franco , De Maria Andrea , Manjili Masoud 
Published: March 2020

10565 Background: Tumor cell recognition by NK cells is mediated by the interaction of activating and inhibitory NK cell receptors with their ligands expressed on tumor cells. In addition, NK cells express adhesion molecules that facilitate formation of the immunological synapse with the tumor targets. Here, we investigated whether the coordinate expression of NK activating receptors and adhesion molecules could provide a signature to segregate breast cancer patients into relapse and relapse-free outcomes. Methods: Gene expression profiling, RT-PCR screening and survival analysis were performed on RNA extracted from primary breast cancers. Tumors were obtained from patients experiencing either 5-8 years relapse-free survival or tumor relapse within 1-3 years following initial treatment. Results: Tumors from patients with a favorable prognosis were characterized by increased expression of genes involved in NK cell interaction with tumor cells and its activation signaling. In particular, up-regulation of Natural Cytotoxicity Receptors (NCRs), leukocyte function-associated antigen 1 (LFA-1), CD226 (DNAM-1) and CD96 was observed in relapse-free patients. Thus, the expression of the NK activating receptors and relevant adhesion molecules involved in NK cell:target interactions can predict relapse free survival in breast cancer patients. Conclusions: Results from the present study, highlighted the effector cooperation between the innate and adaptive immune components within the tumor microenvironment. The NK cells parameters identified in this study, together with the prognostic B and T cell signatures previously reported by us, represent a powerful tool for predicting breast cancer outcome which might be easily introduced in clinical practice.
A randomized phase II trial of doxorubicin plus pemetrexed followed by docetaxel versus doxorubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy (NACT) for early breast cancer: Three-year follow-up data.
Authors: Schneeweiss Andreas , Ruiz Amparo , Manikhas Alexey , Bottini Alberto , Sanchez Rovira Pedro , Mansouri Kambiz , Kazeem Gbenga , Bauknecht Thomas 
Published: March 2020

1059 Background: NACT for early breast cancer allows in vivo chemosensitivity testing. Primary results of this randomized, non-comparative 2-arm study have been published (Schneeweiss et al, Ann Oncol 2011). Here we provide 3-year follow-up data for disease-free survival (DFS) and safety. Methods: 257 patients (pts) with untreated operable T2–T4a–c N0–2 M0 breast cancer were randomly assigned to receive either four cycles of doxorubicin 60 mg/m² plus pemetrexed 500 mg/m² every 3 weeks (q3w) followed by four cycles of docetaxel 100 mg/m² q3w (AP-D; 135 pts), or four cycles of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² q3w followed by four cycles of docetaxel 100 mg/m² q3w (AC-D; 122 pts). Both arms were stratified according to hormone receptor (HR) status (estrogen and/or progesterone receptor positive vs both negative) and study center. Surgery was carried out within 2 months after last chemotherapy. Primary objective was pathological complete response (pCR) rate in the breast (ypT0/is). Secondary objectives included long-term efficacy and safety measures. DFS and adverse event data were collected from all patients for 3 years or until progression or death. The Kaplan-Meier (KM) analysis technique and Cox regression method were used as statistical measures. KM analyses were performed on HR-positive and -negative pts subgroups. Results: As reported earlier, pCR rates were 16.5% for AP-D and 20.2% for AC-D. The 3-year DFS rate was 76% and 77% for AP-D and AC-D, respectively. Cox regression analysis for the overall enrolled population (regardless of treatment) revealed significantly longer DFS in HR-positive than in HR-negative pts (hazard ratio 0.35; 95% CI 0.22–0.58; p < 0.001). In HR-positive pts, the 3-year DFS rate was 88% (95% CI: 81–95%) with AP-D and 83% (95% CI: 74–91%) with AC-D. In HR-negative pts, the 3-year DFS rate was 55% (95% CI: 40–70%) for AP-D and 68% (95% CI: 53–82%) for AC-D. The 3-year follow-up data did not reveal any changes in the safety profile compared to the previously published results. Conclusions: The 3-year DFS rates of both NACTs are in line with published studies.
Retrospective EGFR mutation testing of clinical specimens from the EURTAC trial of erlotinib in non-small cell lung cancer (NSCLC) using a novel allele-specific PCR (AS-PCR) assay.
Authors: Benlloch Susana , Taron Miquel , Botero Maria Luisa , Bertran-Alamillo Jordi , Mayo Clara , Gimenez Capitan Ana , de Aguirre Itziar , Queralt Cristina , Ramirez Jose Luis , Rosell Rafael , Klughammer Barbara , Schlegel Mariette , Chen David , Bordogna Walter , Lee Ju Ruey-Jiuan , Kovach Barbara , O'Donnell Patrick , Wu Lin , Lawrence H. Jeffrey 
Published: March 2020

10596 Background: Anti-EGFR inhibitors are superior to chemotherapy in first-line therapy of advanced EGFR-mutant NSCLC. The EURTAC trial was a randomized Phase III trial of erlotinib vs. chemotherapy in patients with EGFR-mutant NSCLC. Interim results showed significant improvement in progression-free survival (R. Rosell, ASCO 2011). An accurate rapid in vitro diagnostic for EGFR mutations is needed to select patients for this therapy. Methods: Prospective EGFR mutation testing for the trial was performed on laser-capture microdissected tumor cells using a combination of 3 lab-developed tests (LDTs), including a Length Analysis of Fluorescently-labeled PCR (Genescan) method for exon 19 deletions, a Taqman-based PCR assay for exon 21 mutation with laser-capture macrodissected tumor cells, and secondary Sanger sequencing. A subset of samples from the trial was retrospectively tested with an AS-PCR assay (cobas EGFR mutation test) which detects L858R and > 29 exon 19 deletions. The test provides automated results within 8 h; the DNA required can be isolated from one 5-micron tissue section. Four methods were compared: AS-PCR assay, LDT, direct Sanger sequencing and massively parallel sequencing (MPS; 454, Branford, CT). Results: LDT results were obtained for 1044 screened patients. Residual tumor blocks were available for 487 patients (47%), including 303 wild-type, 172 mutant (135 enrolled on the trial) and 12 inconclusive cases by the LDT. Comparison of AS-PCR and LDT results showed a positive percent agreement (PPA) – 93.7% (CI 88.8%, 96.5%), and negative percent agreement (NPA) – 97.5% (94.9%, 98.8%). Comparison of AS-PCR and Sanger results showed a PPA of 96.6% (91.7%, 98.7%) but an NPA of 88.3% (84.1%, 91.5%). Among 34 AS-PCR+/Sanger- case, MPS confirmed the presence of exon 19 deletions in 25 cases and L858R mutations in 7. Direct comparison of AS-PCR and MPS results showed a PPA of 93.1% (88.1%, 96.1%) and NPA of 97.7% (95.0%, 98.9%). Clinical outcomes for cases with mutations detected by the AS-PCR test will be presented. Conclusions: The AS-PCR assay was highly concordant with the LDT and MPS, and more sensitive than Sanger sequencing.
Phase II study of a novel neoadjuvant chemotherapy (NAC) for breast cancer (BC).
Authors: Albino Miguel E. , Cabanillas Fernando , Pavia Orestes Antonio , Bruno Margarita , Echenique Miguel M. , Carlo Victor , Marcial Luisa Vanessa 
Published: March 2020

1060 Background: The goal of this NAC study was to improve the pathologic response of pts with localized BC. Methods: 51 pts with localized BC >1 cm were treated with this novel regimen consisting first of docetaxel 75 mg/m2, epirubicin 80 mg/m2, and cyclophosphamide 500 mg/m2 (TEC) and PEG Filgrastim for 4 cycles. Pretreament PET scan was done and repeated after course 1. Following the 4th course, ER+/HER2- patients received 4 additional TEC cycles if they achieved CR by MRI, or were switched to a non cross-resistant regimen (vinorelbine, bevacizumab, capecitabine) if they had < CR. HER2+ pts were given docetaxel + trastuzumab for 4 additional cycles, or were switched to a different regimen if < PR. MD Anderson residual cancer burden (MDARCB) score was used to measure pathologic response and correlation with several prognostic factors was studied. Results: Median age = 53; 27 were postmenopausal; 42 had invasive ductal carcinoma, 5 invasive lobular; 12 triple negative, 11 HER2+, and 28 ER+ or PR+/HER2-. MDARCB was significantly better in HER-2+ and triple negative tumors (table). ER+ or PR+/Her2- pts had the least favorable MDARCB with none achieving 0 and only 21% attaining MDARCB=1. 59% of pts with > 5% SUV drop attained MDARCB score 0-1 vs 13% with ≤ 5% drop. %Ki-67 correlated well with MDARCB (table). Ki-67 correlated well with receptor status: 85% of Triple Neg or Her2+ pts had Ki-67 >17 vs only 29% of ER+ or PR+/Her2-. Conclusions: a) This novel NAC regimen leads to markedly favorable MDARCB scores in triple negative and Her-2+ cases. b) Several factors may be useful in predicting response to chemotherapy, including receptor status, Ki-67, and PET scan response after 1st chemotherapy course. c) Ki-67 proliferative rate is closely correlated with receptor status. d) Early PET could be used to predict MDARCB. The challenge now is to improve response in ER+ or PR+/Her2- pts. [Table: see text]
The first two lines of chemotherapy for anthracycline-naïve metastatic breast cancer: A comparative study of efficacy between anthracyclines and nonanthracyclines.
Authors: Chen Wei-Wu , Chang Twan Ying , Huang Shu-Min , Lin Ching-Hung , Hsu Chiun , Cheng Ann-Lii , Lu Yen-Shen 
Published: March 2020

1061 Background: For anthracycline-naïve metastatic breast cancer (AN-MBC) patients, past evidence indicated that anthracyclines are beneficial in the first-two lines of palliative chemotherapy but with considerable toxicities. However, with the provision of newer chemotherapies, comparative studies addressing the efficacy between anthracyclines and non-anthracyclines in the first-two lines of palliative chemotherapy for AN-MBC were lacking. Methods: We collectedclinicopathological characteristics of AN-MBC patients who had received palliative chemotherapy in National Taiwan University Hospital between 2001 and 2006. Patients were classified as anthracycline or non-anthracycline group according to the first-two lines of chemotherapy. Kaplan-Meier method and log-rank test were used for the estimation and comparison of both overall survival (OS) and time to treatment failure of the first-two lines (TTF2).Cox proportional hazard model was used for OS and TTF2. Best composite response rate (BCRR) were compared with logistic regression test. Results: A total of 109 (43.1%) patients in the anthracycline group and 144 (56.9%) patients in non-anthracycline group were analyzed. Between these two groups, the distributions of clinicopathological variables were generally similar and their median OS (33.3 vs 34.2 months, p = 0.179), TTF2 (13.3 vs 12.7 months, p = 0.104), and BCRR (59.5 vs 61.1%, p = 0.81) were not significantly different. Subgroup analysis showed that patients in the anthracycline group had a trend toward better OS in the estrogen receptor (ER) negative/ human epidermal growth factor receptor type II (HER2) positive subtype (median OS 58.0 vs 31.2 months, p = 0.081). In multivariate analysis, patients in the anthracycline group had a trend toward better OS (HR 0.72, 95% CI 0.52 - 1.00, p = 0.052). However, the exclusion of ER-/Her2+ subtype attenuated the impact of early anthracycline treatment on OS (HR 0.82, 95% CI 0.56 - 1.18, p = 0.28). Conclusions: Our study demonstrated that anthracyclines may not be mandatory in the first-two lines of palliative chemotherapy for AN-MBC but may be more beneficial to ER-/Her2+ subtype patients.
Use of proteomic analysis of LKB1/AMPK/mTOR pathways to identify IGF-1R pathway upregulation with LKB1 loss or mTOR inhibition in NSCLC: Implications for targeted combinations.
Authors: Yilmaz Emrullah , Byers Lauren Averett , Diao Lixia , Giri Uma , Gudikote Jayanthi , Fan You Hong , Wang Jing , Coombes Kevin R. , Girard Luc , Minna John D. , Heymach John 
Published: March 2020

10612 Background: LKB1 is a serine/threonine kinase which is mutated in 20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling. We investigated the signaling pathways modulated by LKB1 mutations and by mTOR inhibition in NSCLC. Methods: Protein expression in cell lines was measured by reverse phase protein array. Differences in protein expression at baseline in LKB1 wild-type versus mutant cell lines and the effects of protein modulation by treatment were assessed by ANOVA. Results: LKB1 mutant cell lines had lower expression of phosphorylated AMPK and TSC (p<0.01 for both) consistent with prior observations. In addition, mutant cell lines expressed higher levels of proteins in the IGF1R pathway including IGFR1b (p<0.0001); AIB1, which is known to upregulate IGF1 (p<0.0001); and IGFBP2 (p=0.016). LKB1 mutant cell lines (n=11/25) were 1.5-fold more sensitive to the AMPK activator metformin, although this did not reach statistical significance (p=0.10). Expression levels of IGF1R pathway proteins increased significantly after 48h treatment with metformin, the mTOR inhibitor temsirolimus, and the dual PI3K/mTOR inhibitor PI103. For example, IGFBP2 and AIB1 were elevated after metformin treatment (p=0.02 and 0.005, respectively); IRS1 and IGFR1 were elevated after temsirolimus or PI103 (p<0.05 for both). Following treatment with metformin and temsirolimus, there was also increased pAkt, a downstream target of IGF1R and activator of mTOR (p<0.01 for both). Modulation of the IGF1R pathway by these drugs was independent of LKB1 mutation status. Conclusions: LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFB2 and AIB1, suggesting that IGFR may be a potential therapeutic target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway possibly as a feedback mechanism. These results support the investigation of IGFR inhibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.
Zoledronic acid effect on circulating RANK/RANK-l/OPG axis in cancer patients.
Authors: Ibrahim Toni , Mercatali Laura , Ricci Marianna , Scarpi Emanuela , Fabbri Francesca , Liverani Chiara , Nicoletti Stefania Vittoria, Luisa , Ricci Rossana , Serra Patrizia , Amadori Dino 
Published: March 2020

10615 Background: Bone metastasis disrupts bone integrity through loss of the balance between osteoclastic-mediated osteolysis and osteoblastic osteogenesis. The RANK/RANK-L/OPG axis governs osteoclastogenesis and bone resorption. We evaluated the trend of markers over time. Secondary aims were to study the predictive role of different circulating markers in the response to Zoledronic Acid (ZA) with respect to objective response and to skeletal-related events (SREs). Methods: The study prospectively evaluated levels of RANK, RANKL and OPG transcripts by Real-Time PCR and VEGF and NTX expression by ELISA in the peripheral blood of 49 consecutive patients with advanced breast, prostate or lung cancer (36, 7 and 6, respectively). Enrolled patients were at first diagnosis of bone metastases and had not previously undergone treatment with bisphosphonates. Patients received the standard schedule of ZA (4 mg infusion every 28 days) for about 12 months, undergoing blood tests and instrumental evaluation before the first infusion of ZA and every 4 months thereafter. Results: Median RANKL values after 12 infusions of ZA had decreased by 22% with respect to baseline whereas OPG, had increased by about 96%, with a 56% decrease in the RANKL/OPG ratio. NTX decreased over time (p<0.0001). On the basis of ROC curve analysis, RANKL was the most accurate marker for bone response with an AUC of 0.74 (95% CI 0.54-0.93). No correlations were found between circulating markers and SREs. Conclusions: The present work is one of the few prospective studies carried out on the circulating markers that are potentially associated with bone metastases. Our findings would seem to indicate that ZA decreases osteoclast activity through RANK/RANKL/OPG pathway modulation and that RANKL may play a role in the prediction of objective response to ZA. Confirmation of results is needed in a larger case series.
Identification and validation of plasma protein biomarker panels for breast cancer diagnosis by using multiple reaction monitoring-based mass spectrometry.
Authors: Moon Hyeong-Gon , Kang Un-Beom , Han Wonshik , Im Seock-Ah , Noh Dong-Young 
Published: March 2020

10621 Background: Multiple reaction monitoring-based mass spectrometry (MRM-MS) has the ability to perform a wide range of proteome analysis in a single experiment using a small volume of specimen. We aimed to develop a plasma protein signature for breast cancer diagnosis using the MRM-MS technology. Methods: Previously, we have identified lists of breast cancer-related proteins from various models of proteomic discovery including cancer plasma vs healthy plasma, cancer cell line secretome vs non-tumorigenic cell line secretome, cancer tissue vs normal tissue, and literature search. Based on these protein panels, total of 29 proteins were selected for further experiments. We verified and validated the protein signature in two independent cohorts of breast cancer patients and healthy women. Results: In the verification cohort of 80 breast cancer patients and 80 healthy women, MRM-MS showed significant differences in plasma concentration for 11 proteins. Among them, the difference was not significant for 4 proteins when the cases were limited to stage I and II patients. Based on p values and consistent expression level along the AJCC stages, we have created a plasma protein signature comprised of 3 plasma proteins. The 3 plasma protein signature effectively discriminated cancer and healthy cases with the AUC of 0.831 (sensitivity 78.7%, specificity 78.7%). The performance of the 3 plasma protein signature was validated in the cohort of 100 cancer patients and 100 healthy women. The accuracy of the 3 protein signature was still meaningful with the AUC of 0.746 and 0.797 for all stages and stage I or II patients, respectively. Conclusions: The 3 plasma protein signature for breast cancer diagnosis, developed by the MRM-MS technology, showed promising results in the present study.
New mechanistic insights into possible radiobiologic and pathophysiologic explanations for unexpectedly impressive outcomes data observed for hormone-refractary metastatic prostate cancer patients treated with radium 223.
Authors: Macklis Roger M. , Sartor A. Oliver 
Published: March 2020

10623 Background: The ALSYMPCA Trial of 223Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223Ra plus SOC vs best SOC. This trial was stopped early after 922 patients enrolled at over 100 centers achieved primary (overall survival) and all secondary endpoints including median survived (14 vs 11.2 m) time to first SRE (13.6 m vs 8.4 m) and time to PSA progression.These unexpectedly positive results prompted us to review some of the unique aspects of alpha-particle radiobiology and ultra-short range molecular targeting capabilities. Methods: Literature analysis. Results: The highly energetic alpha particles such as those released during decay of 223Ra (T1/2 = 11.4 mins) display unique radiobiologic and dosimetric aspects. The nuclear dose required in vitro for approximately 90% target cell kill is less than 1 Gy and electron micrographs shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. Bovine aortic endothelial cells exposed to alpha particle radiation indicate that the radiobiologic effects depend heavily on cell culture condition with nonuniform DNA strand break damage observed in isolated detached cells. The subcellular alpha particle path length appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. 223Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be effective in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing subcellular damage accumulation to target cell groups.
Low-dose, short-course sunitinib may normalize tumor vasculature and improve tumor blood flow to enhance chemotherapy efficacy in breast cancers.
Authors: Lee Soo-Chin , Wong Andrea LA , Ng Thian C , Thng Choon Hua , Wang Ting Ting , Tiemsim Maricel Cordero , Ong Eugene , Koh Tong San , Cheong Dennis , Voon Pei-Jye , Soh I Peng Thomas , Chan Ching-Wan , Iau Philip , Tan Chee Seng , Pang Angela , Goh Boon C. 
Published: March 2020

1064 Background: Small molecule VEGFR inhibitors (VEGFR-I) have failed to improve outcome with chemotherapy in most solid tumors. Continuous administration of a potent VEGFR-I may destroy vasculature and impede drug delivery; in contrast, low-dose, short-course VEGFR-I before chemotherapy may normalize tumor vasculature and enhance drug delivery. Methods: We conducted a phase Ib followed by phase II randomized study in patients with measurable primary breast tumors using low-dose sunitinib (Su) for 1 week prior to doxorubicin/cyclophosphamide (AC) and measured tumor blood flow with DCE-MRI and microvessel density and pericyte recoverage with CD31 and α-smooth muscle actin (SMA) staining on tumor biopsies, at baseline, after 1 week of Su, and 2 weeks after cycle 1 AC. Patients in phase Ib received 12.5-25mg Su prior to AC; in phase II, patients were randomized to AC+/-12.5mg Su. Results: 21 patients have been enrolled, including 3 patients on 25mg Su+AC, 11 on 12.5mg Su+AC, and 7 on AC alone. After 1 week of 25mg Su, 2/3 patients had reduced tumor blood flow on DCE-MRI indicating anti-angiogenic effects. After 1 week of 12.5mg Su, significant increase in tumor fractional plasma volume (Vp) occurred (+28%±28%, p=0.025) suggesting increased perfusion, followed by decrease 2 weeks after AC (-33%±26%,p=0.035) corresponding to mean tumor size change of -17±15%, while no significant Vp changes occurred with AC alone (p=0.823); CD31 expression reduced (20.7 vs 15.7, p=0.173) while SMA/CD31 double staining increased (2.45 vs 7.34, p=0.046) indicating lower microvessel density and normalization of residual vasculature, which was not seen with AC alone (CD31, p=0.434; CD31/SMA, p=0.605). The main toxicity of Su+AC and AC alone was febrile neutropenia (29% vs 43%). 14 patients had surgery with pathological complete response in 1/6 patients who received 12.5mg Su+AC. Conclusions: 25mg Su for 1 week can reduce tumor blood flow, suggesting that concomitant standard dose Su may compromise drug delivery. Low dose 12.5mg Su for 1 week is sufficient to normalize tumor vasculature and increase tumor fractional plasma volume, and may potentially improve drug delivery and treatment outcome.