bluuebunny/crossref_metadata_2025 huggingface dataset:
ALK amplification and crizotinib sensitivity in non-small cell lung cancer cell lines and patients report.
Authors: Khadija Kalai , Auger Nathalie , Lueza Beranger , Commo Frederic , Valent Alexander , Rousseau Vanessa , Dorvault Nicolas , Friboulet Luc , Olaussen Ken , Rajpar Laetitia , Planchard David , Lacroix Ludovic , Pignon Jean-Pierre , Soria Jean-Charles , Besse Benjamin
Published: March 2020

10556

Background: ALK high copy number (HCN) seems to be a frequent event, described in 13-17% of Non-small cell lung cancer (NSCLC). The goal of this study was to describe ALK genomic aberrations on NSCLC patients and cell lines, to explore the ALK HCN response to crizotinib through in vitro assays and to report three patients case. Methods: 191 Paraffin embedded specimens from advanced NSCLC patients and 27 NSCLC cancer cell lines were screened for ALK copy number by fluorescent in situ hybridization (FISH). Crizotinib sensitivity was evaluated in 9 cell lines through WST1 assays and clonogenic tests. Three patients exhibiting ALK HCN were assessed for response to crizotinib. Results: EML4-ALK translocation was present in 22 pts (11.5%). 21 pts (11%) exhibited over 6 copies of ALK. 6 (22%) cell lines displayed more than 5 copies of ALK, 19 (70%) presented a gain of 3 or 4 ALK copy number, only one cell line exhibited normal ALK copies and one harbored EML4-ALK translocation. FISH with CEP2 revealed a polysomy of chromosome 2 in cases with ALK HCN.Out of the 9 cell lines tested, 4 ALK HCN cell lines (H661, A427, BEN, H1299) exhibited increased sensitivity for crizotinib vs. 3 low ALK copy number (LCN) cell lines (H1975, H1651, H1650) with a low sensitivity. Median IC50 with crizotinib values was1750 nM [300-2800nM] in ALK HCN cell lines vs 4500 nM [800-8000nM] in ALK LCN cell lines, p=0.35. 3 patients with ALK HCN tumor received crizotinib ( in 4th , 5th and 6th -line therapy) for 2, 3 and 5 months with stable disease as best response and clinical benefit in 2 pts. Conclusions: ALK HCN may predict sensitivity to crizotinib. A clinical study is planned in ALK HCN pts.
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.
Efficacy of low-dose capecitabine in metastatic breast cancer.
Authors: Bertelsen Caitlin , Ji Lingyun , Russell Christy Ann , Spicer Darcy V. , Garcia Agustin , Sposto Richard , Tripathy Debu
Published: March 2020

1065

Background: The FDA-approved dose of capecitabine (cape) of 1250mg/m2 twice daily (BID) is associated with treatment-limiting toxicities. Published reports suggest that lower starting doses of cape can be as effective as the approved dose in treating metastatic breast cancer (MBC). We compared the efficacy of lower than previously published doses of cape with results of registrational Phase III trials using the approved dose. Methods: We performed a retrospective analysis of patients treated at the University of Southern California hospitals who received cape as the first, second, or third line of chemotherapy for MBC to determine the progression-free survival (PFS) associated with low starting doses. The primary endpoint was PFS among patients with measurable disease, and secondary aims were to analyze the relationships between PFS and various clinical characteristics for all patients. Results: Patients (n=84) received a median cape dose of 565 mg/m2 BID, often administered as a flat dose (not adjusted for body surface area) of 1000 mg BID. Median PFS among patients with measurable disease (n=62) was 4.1 months (95% confidence interval or CI = 2.9-5.7), which was similar to the median PFS values of 4.4 months (95% CI = 4.14-5.42, n=480) (Sparano et al. JCO 2010;28:3256) and 4.2 months (95% CI = 3.81-4.50, n=377) (Thomas et al. JCO 2008;25:5210) for single-agent cape reported in the major trials with similar eligibility criteria. Among all patients, PFS was shorter in measurable disease, triple negative and HER2+ subtypes, and was similar in all lines of therapy. Only two patients (2.4%) discontinued cape due to toxicity. Conclusions: These data support the efficacy of very low doses of cape for MBC. Prospective randomized controlled trials testing lower starting doses of cape are needed to optimize the benefit/risk ratio. [Table: see text]
Cancer stem cell markers in locally advanced breast cancer.
Authors: Tiezzi Daniel G. , Sicchieri Renata D , Antonio Heriton MR , Mouro Larissa R , da Silva Joao Santana , de Andrade Jurandyr Moreira ,   Breast Disease Division - FMRP
Published: March 2020

1075

Background: the expressions of CD44/CD24, CXCR4 and ABCG2 have been reported as potential breast cancer stem-like cell (CSLC) markers. The association between the quantity of CSLCs and the response to neoadjuvant chemotherapy (NACT) remains unclear. Methods: we prospectively analyzed the expression of CD44/CD24, CXCR4 and ABCG2 in 20 patients with locally advanced or metastatic (LAMBC) invasive ductal carcinomas of the breast subjected to NACT. The mammosphere assay (Mammocult) was studied in 10 samples. Patients’ mean age was 55.6 ± 8.2 yo. According to clinical stage (CS), 5 patients were IIb, 4 - IIIa, 8 - IIIb and 3 - IV. The mean clinical tumor diameter was 6.3 ± 2.8cm. The ER, PgR and HER2 positive expression rates were 50%, 45% and 50%, respectively. Ten patients were treated with EC-T, eight were treated with EC-TH (HER2+) and two were treated with FEC75 combination as NACT. The median percentage CD44+/CD24-, CXCR4+, ABCG2+ and ESA+ cells within Lin- cells were determined by flow cytometry in fresh sampled tumors after tissue digestion. The relationship between flow cytometry analyses and clinical and pathological response to therapy was analyzed. Results: complete clinical response (cCR) and complete pathological response (pCR) was observed in 9 (45%) and 5 (25%) patients. We did not observe a significant association between pCR and ER, PgR or HER2 expression. We observed and association between the pCR with percentage of ABCG2+ cells within the tumor and with the number of mammospheres. No correlation between pCR and CD44+/CD24- cell population within the tumor was observed. The median percentage of ESA+/Lin-/ABCG2+ cells within the tumor in pCR patients was 0.6% and 3.5% in patients with no pCR (p= 0.02). The median number of sphere formation was 5/100 cells and 0.9/1000 cells in pCR and non-pCR patients, respectively (p= 0.02). Interestingly, there was a positive correlation between ABCG2 expression and the number of mammosfere formation (r= 0.66; p= 0.03). This correlation was not significant comparing to CD44+/CD24- cells or CXCR4. Conclusions: the percentage of ABCG2+ cancer cells within the tumor and the number of mammosphere formation are predictive factors for pCR in LAMBC patients subjected to NACT. ABCG2 is a potential marker for CSLCs.
BCL2 protein in prediction of relapse in triple-negative breast cancer (TNBC) treated with adjuvant anthracycline-based chemotherapy.
Authors: Bouchalova Katerina , Svoboda Marek , Kharaishvili Gvantsa , Radova Lenka , Bouchal Jan , Trojanec Radek , Koudelakova Vladimira , Hajduch Marian , Cwiertka Karel , Kolar Zdenek
Published: March 2020

1087

Background: Preclinical data show an association of BCL2 expression and resistance to anthracyclines. The absence of BCL2 expression in prechemotherapy samples is associated with a higher probability of pathological complete response to neoadjuvant doxorubicin-based chemotherapy. The aim of our research is identification of markers predicting sensitivity to adjuvant treatment in TNBC. Here we focus on BCL2 protein as a putative predictor of sensitivity to adjuvant anthracycline-based chemotherapy. The objective was to determine whether BCL2 expression predicts relapse in TNBC patients treated with anthracycline-based regimens. Methods: The study included 187 patients with TNBC, 178 of whom were treated with adjuvant chemotherapy (164 had anthracyclines). BCL2 analysis was performed using IHC, proportion score and intensity score were counted. The data were analysed with software Statistica and R. Results: High BCL2 expression predicts poor relapse free survival (RFS) in patients treated with adjuvant anthracycline-based regimens (logrank p=.035, hazard ratio, HR 2.37, 95%CI 1.04-5.41). High BCL2 predicts trend to poor overall survival (OS) in patients treated with adjuvant anthracycline-based regimens (logrank p=0.075, HR 2.31, 95%CI 0.90-5.97). In univariate analysis of anthracycline treated patients, stage (RFS p=.0004, OS p=.0005), size (RFS p=.003, OS p=.00009) and nodal status (RFS p=0.018, OS p=.028) were associated with outcome, as well. In multivariate analysis of athracycline treated patients, BCL2, size and nodal status had an independent predictive significance for both RFS (p=.005, p=.056, p=.003) (logrank test, p=0.0004) and OS (p=.014, p=.006, p=.012) (logrank test p=0.0007). Conclusions: This study is the first to prove that high BCL2 expression predicts poor outcome in TNBC treated with adjuvant anthracycline-based chemotherapy. BCL2 expression could facilitate decision making on adjuvant treatment in TNBC patients and its assessment should be included in standard diagnostics. In patients with high BCL2 expression other types of adjuvant treatment should be considered. Grants: IGA NS10286,IGA NS10357-3 and Biomedreg CZ.1.05/2.1.00/01.0030.
Management of antiangiogenics’ renovascular safety in breast cancer subgroup and intermediate results of the MARS study.
Authors: Daniel Catherine , Janus Nicolas , Rey Jean-Baptiste , Beuzeboc Philippe , Ray-Coquard Isabelle , Gligorov Joseph , Spano Jean-Philippe , Thery Jean Christophe , Jouannaud Christelle , Goldwasser Francois , Mir Olivier , Morere Jean F. , Oudard Stephane , Azizi Michel , Dorent Richard , Deray Gilbert , Launay-Vacher Vincent
Published: March 2020

1095

Background: Hypertension (HTN) and proteinuria (Pu) are class-side-effects of anti-VEGF drugs (AVD), related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of AVD in the clinical setting. Methods: The MARS study is a multicentric prospective observational study of the renovascular safety of AVD in AVD-naive pts. 7 centres from 2009 to 2011. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and Pu. This sub-group analysis presents the intermediate results for the 1st 155 pts with breast cancer (BC) receiving bevacizumab who completed the 1-year follow-up (f/u) (out of 337 BC pts in total). Results: Median age at inclusion: 62 years. Bone, visceral and cerebral metastasis frequencies were 74.2, 51.6 and 5.2%, respectively. Diabetes and HTN prevalences were 3.9% and 10.3%, respectively. Baseline renal assessment retrieved: Pu 14.2%, Hu 8.4%, aMDRD 98.2 ml/min/1.73m2 and 2 pts with aMDRD<60. The incidence of de novo Pu during f/u was 15% (Table). 59.1% of pts with Pu at inclusion improved. Among pts with de novo Pu, 40.0% afterwards improved/normalized. No grade 3/4 Pu has been reported and no hematuria. 12.9% developed HTN. Moreover, renal function decreased by -3.2 ml/min/1.73m2/year and 4 pts had aMDRD<60 at the end of f/u. 32.2% increased their SCr: 27.1% grade 1, 4.5% grade 2, and 0.6% grade 3. All pts with grade 2-3 returned to normal or grade 1. No thrombotic micro-angiopathy (TMA) has been reported. Conclusions: These results show that 1) TMA remains rare, 2) Pu developed in 15% of pts, with no grade 3/4, 3) less than 13% developed HTN and 4) renal function was only slightly impaired with transient elevations in SCr. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
Patterns of regional node irradiation therapy following breast-conserving surgery: Report from the National Cancer Data Base 2003-2007.
Authors: Hou Ningqi , Yao Katharine , Jaskowiak Nora T. , Hasan Yasmin , Winchester David J. , Winchester David Porter , Huo Dezheng
Published: March 2020

1101

Background: A recent randomized trial (MA.20) showed that regional nodal irradiation (RNI) in addition to breast irradiation in high risk node negative and 1-3 node positive patients undergoing breast-conserving therapy (BCT) reduced the risk of recurrence and improved disease-free survival. We investigated the trends of RNI use in the United States and related factors for the use of RNI using the National Cancer Data Base. Methods: This study includes 292,598 stage I-III breast cancer patients without neoadjuvant therapy who underwent BCT from 2003-2007. We investigated pathological, patient, and facility factors related to RNI use, by multivariable logistic regression, with odds ratio (OR) estimations. Results: The proportion of radiotherapy use after BCT slightly declined from 78.6% in 2003 to 75.6% in 2007. The use of breast irradiation plus RNI decreased from 10.8% in 2003 to 8.3% in 2007 (p<0.0001). The number of tumor positive lymph nodes strongly determined the use of additional RNI: 4.4% patients with negative nodes, 22.8% patients with 1-3 nodes, and 39.7% patients with 4 or more nodes received breast irradiation plus RNI after undergoing BCT (p<0.0001). The proportion of patients undergoing RNI significantly decreased over the study period from 43.3% to 37.2% in the 4+ node positive group, and from 23.6% to 22.0% in the 1-3 node positive group. At comprehensive community cancer centers, 25.5% patients with 1-3 positive nodes were treated with breast irradiation plus RNI (vs. 23.2% in community cancer centers and 21.1% in academic/research cancer centers). Among node negative patients, 11.5% of those with tumor size greater than 5 cm received additional RNI, compared to 4.3% in patients with tumors less than 5cm (p<0.0001). Other significant factors related to RNI use included higher tumor grade, younger age, facility location, and facility volume. Conclusions: The use of RNI varies by number of tumor positive nodes and facility factors. Only 22.8% of patients with 1-3 positive nodes underwent RNI. Future studies are needed to determine if the use of RNI will increase after publication of the MA.20 trial especially for the 1-3 node positive group.
Breast cancer multifocality-multicentricity and survival outcomes.
Authors: Lynch Siobhan P. , Lei Xiudong , Chavez-Mac Gregor Mariana , Hsu Limin , Meric-Bernstam Funda , Buchholz Thomas A. , Zhang Hong , Hortobagyi Gabriel N. , Valero Vicente , Gonzalez-Angulo Ana M.
Published: March 2020

1104

Background: Studies have consistently shown a correlation between multifocal (MF) and multicentric (MC) breast cancers and the rate and extent of lymph node metastases, but the literature is divided on whether there is a corresponding impact on survival outcomes. In the absence of compelling evidence to dictate otherwise, the convention according to current TNM staging guidelines has been to stage and treat MF and MC cancers according to the diameter of the largest lesions, without taking other foci of disease into consideration. We evaluated a large single institution cohort of MF and MC breast cancers to determine their frequency, clinico-pathological characteristics and effect on survival outcomes. Methods: MF and MC were defined pathologically as more than one lesion in the same quadrant and more than one lesion in separate quadrants, respectively. Patients were categorized by presence or absence of MF or MC disease. Kaplan-Meier product limit method was used to calculate relapse-free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. Results: Out of 3924 patients, 942 (24%) had MF (n=695) or MC (n=247) disease. MF and MC disease was associated with higher T-stages (T2 26% vs. 21.6%; T3 7.4% vs. 2.3%, P<0.001), higher nuclear grade (grade 3 44% vs. 38.2%, P<0.001), lymphovascular invasion (26.2% vs. 19.3%, P<0.001) and lymph node metastases (43.1% vs. 27.3%, P<0.001). After a median follow up of 51 months, MC but not MF breast cancers were associated with significantly worse 5-year RFS (90% vs. 95%, P=0.02) and BCSS (95% vs. 97%, P=0.01), and a trend towards worse 5-year OS (92% vs. 93%, P=0.08). After controlling for other risk factors, multifocality and multicentricity did not have an independent impact on RFS, BCSS or OS. This was true for the subset of T1N0 breast cancers as well. Conclusions: MF and MC breast cancers occurred in 24% of the cases and were associated with poor prognostic factors, but they were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T-stage.
Role of axillary ultrasound after neoadjuvant chemotherapy in women with node-positive breast cancer (T1-4, N1-2, M0) at initial diagnosis (ACOSOG Z1071).
Authors: Le-Petross Huong T. , McCall Linda Mackie , Hunt Kelly , Mittendorf Elizabeth Ann , Ahrendt Gretchen M. , Wilke Lee G , Leitch A. Marilyn , Taback Bret , Boughey Judy Caroline ,   American College of Surgeons Oncology Group
Published: March 2020

1107

Background: The role of axillary ultrasound (AUS) after neoadjuvant chemotherapy (NAC) to assess for residual nodal disease in patients presenting with node positive breast cancer remains unclear. ACOSOG Z1071 is a prospective multi-institutional trial evaluating sentinel node biopsy in patients with biopsy proven node positive breast cancer (T0-4, N1-2, M0) receiving NAC. Herein we report on the secondary objective evaluating the correlation of lymph node (LN) features on AUS with residual nodal disease. Methods: AUS images from diagnosis and after NAC were centrally reviewed for cortex size, LN size and LN morphology. Morphologic features were defined as: type I, no visible cortex, type II, < 3 mm hypoechoic cortex, type III, > 3mm hypoechoic cortex, type IV, generalized lobulated hypoechoic cortex, type V, focal hypoechoic cortical lobulation, and type VI, totally hypoechoic node with no hilum. Type I and II are considered normal. Results: Surgical and imaging data are available on 294 patients. Median age was 50 years (range 23-93 years), mean initial tumor size 3cm (0 to 15cm) and clinical stage II in 64.5% and III in 35.5%. The maximum LN diameter decreased after NAC (mean 22mm pre-NAC to 14mm post-NAC)(p<0.0001); however, there was no significant difference after NAC between the pathologically N+ (13mm, range 5-46mm) and N0 cases (12mm, range 3-32mm)(p=0.13). LN cortical thickness correlated with residual nodal disease after NAC (p-value = 0.04). Using a cutoff point of cortical thickness of 3 mm, the sensitivity was 33% (48/145) and specificity 80% (66/82). AUS morphological features after NAC was associated with false negative rate 62%, false positive rate 28%, sensitivity 38%, and specificity 72%. Conclusions: AUS after NAC is useful to assess nodal response. Cortical thickness was the best predictor of residual nodal metastasis. LN size and morphological features do not reliably exclude residual nodal metastasis in patients after NAC. [Table: see text]
Accuracy of breast MRI in predicting pathologic tumor size.
Authors: Caprio Kimberly Anne , Chagpar Anees B. , Hooley Regina , Tavassoli Fattaneh , Honarpishe Helen , Lannin Donald R. , Killelea Brigid K. , Horowitz Nina Ruth
Published: March 2020

1109

Background: MRI use as a preoperative planning tool is increasing in women with breast cancer, yet the correlation between MRI and pathologic size of cancers is unclear. The purpose of this study was to determine the accuracy of MRI in predicting pathologic tumor size, and factors that affect this correlation. Methods: Clinicopathologic and imaging data from 84 patients diagnosed with invasive or in situ breast cancer from September 2010 to October 2011 who had preoperative MRI were reviewed. 12 patients who had neoadjuvant chemotherapy were excluded. MRI detected 147 lesions in the remaining 72 patients. Concordance between MRI and pathology size was determined using Spearman rho coefficients, and factors affecting the accuracy of MRI in predicting tumor size within +/- 0.5 cm were determined. Results: There was a modest correlation between MRI and pathology size for all MRI detected lesions (benign or malignant) with a Spearman coefficient of 0.53. Of the 147 MRI detected lesions, 45 (30.6%) had pathologic and MRI size correlating within +/- 0.5 cm; 76 (51.7%) were overestimated (>0.5cm) by MRI, and 26 (17.7%) were underestimated (>0.5cm). 101 (68.7%) of the 147 lesions were found to be malignant (either with invasive disease or DCIS). In this subgroup, 35 lesions (34.7%) had an MRI size within +/- 0.5 cm of the pathologic size; 40 (39.6%) were overestimated by MRI and 26 (25.7%) were underestimated. Patient age, tumor histology, LVI and grade did not predict concordance between pathologic and MRI size. However, small MRI lesion size more accurately correlated with pathologic tumor size. While 51.1% of tumors that had concordant MRI and pathologic findings within 0.5 cm were <1 cm on MRI, no tumor found to be > 5 cm on MRI was within +/-0.5 cm on final pathology (p=0.001). Conclusions: MRI accurately predicts pathologic tumor size only when the size of the lesion on MRI is <1 cm.
The impact of primary surgery on stage IV breast cancer.
Authors: Harris Ella , Kell Malcolm R. , Salman Reem , Stokes Maurice , Gorey Tom
Published: March 2020

1113

Background: The role of primary surgery in metastatic breast cancer is unclear. Here in we have performed metaanalysis on available data to assess the role of surgery on oncological outcome in patients with stage IV breast cancer. Methods: A comprehensive search for published trials that examined outcome following removal of primary disease in stage IV breast cancer was performed using MEDLINE and cross referencing available data. Reviews of each study were conducted, and data were extracted. Primary outcome was overall survival related to surgical removal of primary disease. Results: We identified 15 relevant studies of which 10 were appropriate for analysis. Data was available on 28,693 patients with stage IV disease, of whom 52.8% underwent removal of the primary carcinoma. Patients undergoing primary surgery in this setting were more likely to be alive at 3 years 40% vs. 22% (OR 2.32 CI 2.08-2.6, p<0.01 (surgery vs. no surgery)). Analysis of subgroups for selection to surgery or not, favoured smaller tumours, fewer comorbidities, fewer metastases (p<0.01). There was no difference between the two groups in location of metastases, grade of tumour or receptor status. Conclusions: Patients undergoing removal of primary carcinoma in the setting of stage IV breast cancer appear to have an improved overall survival. However the available data suggest that these surgical patients probably have better prognosis stage IV disease than those patients not undergoing surgery.