bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic effect of beta blockers (BB) in triple-negative breast cancer (TNBC) patients.
Authors: Munzone Elisabetta , Botteri Edoardo , Rotmensz Nicole , Cipolla Carlo Maria , Zanelotti Arnaldo , Adamoli Laura , Viale Giuseppe , Goldhirsch Aron , Gandini Sara 
Published: March 2020

1061 Background: BB drugs have been used for decades worldwide, typically to treat hypertension and arrhythmias. Despite its therapeutic indication, evidence from recent epidemiological studies suggested that BB intake can improve prognosis of patients (pts) with cancer. With the present study we aimed at assessing whether BB intake is associated with improved prognosis in postmenopausal pts with TNBC, which represents one of the most aggressive cancers. Methods: We retrospectively identified 659 postmenopausal pts operated between 1997 and 2008 at the European Institute of Oncology, Milan, for a primary TNBC. Pts with advanced disease at diagnosis, presurgical systemic treatment or history of other cancers were excluded. The effect of BB intake on the risk of breast cancer recurrence and death from breast cancer (BC) was evaluated through competing risk survival analyses and multivariable Cox regression models. Results: At the time of cancer diagnosis, 61 pts (9.3%) out of 659 were currently using BB, while 598 (90.7%) were not. Median age was 63 years for the BB users and 60 years for the non-users (p value 0.048). All other characteristics—such as tumor size, lymph-nodal involvement, Ki-67, tumor grade, perivascular invasion, type of surgery and adjuvant therapy—were equally distributed between BB users and non-users. Median follow-up was 6 years for both groups. The 5-year cumulative incidence of BC recurrences was 11.7% and 24.1% for BB users and non-users, respectively (p = 0.030). After adjusting for age, tumor size, lymph nodal involvement, grade, perivascular invasion and use of other antihypertensive drugs, the beneficial impact of BB use remained statistically significant, with an hazard ratio of 0.44 (95% CI 0.21-0.98; p = 0.044). The 5-year cumulative incidence of BC deaths was 8.2% and 12.5% for BB users and non-users, respectively (p = 0.185). Hypertension and antihypertensive drugs other than BB did not have any significant impact on recurrence and survival. Conclusions: In this series of postmenopausal pts with primary TNBC, BB intake was associated with a significantly decreased risk of BC recurrence. Additional studies evaluating the potential benefits of BB on cancer prognosis are warranted.
Androgen receptor (AR), E-cadherin, and Ki-67 as prognostic markers in triple-negative breast cancer (TNBC).
Authors: Ricciardi Giuseppina R. R. , Adamo Barbara , Ferraro Giuseppa , Franchina Tindara , Zanghì Mariangela , Buda Carmelo , Trimarchi Giuseppe , Cardia Roberta , Tuccari Giovanni , Adamo Vincenzo 
Published: March 2020

1062 Background: TNBC is an aggressive subset of breast cancer (BC) with central nervous system and visceral metastatic involvement and it represents a molecular subtype without specific target therapy. Methods: This observational, retrospectivestudy included 45 TNBC. The aim of this study was to evaluate the expression of some molecular determinants such as the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival.Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients (pts) defined TNBC, since ER and PgR were 0% and HER2 negative (IHC score 0/1 or FISH not amplified). Results: Median age was 58.8 years (range 39-77). The main histological type was ductal in 35 pts (77.7%), lobular in 7 (15.5%), medullary in 3(6.6%). 29 pts (64.4%) had a G3 tumor. Tumor stage was: I 6/45 (13.3%), IIA 21/45 (46.6%), IIIA 11/45 (24.4%), IIIB 3/45 (6.6%) and IV 4/45 (8.8%). All patients received treatments; the most frequently used regimens were anthracycline and taxanes. The androgen receptor was positive (IHC >10%) in 12/45 (26.6%). E-cadherin expression was semi-quantitatively analyzed according to the percentage of cells showing membrane positivity: 0 (0 to 10%); 1+ (10 to 30%); 2+ (30 to 70%); 3+ (> 70%). E-cadherin expression was considered positive if the score was ≥ 2, and negative when score was ≤ 1. This expression was negative in 24/45 (53.3%) cases. The Ki-67 index was ≥ 25% in 17/45(37.7%). The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with the ductal histotype and G3 tumors (p < 0.001). Multivariate analysis showed that the patients with AR and E-cadherin negative but Ki-67 positive expression showed significantly (p < 0.001) worse overall survival time than those with either AR and E-cadherin positive but Ki-67 negative expression. Conclusions: Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC.
Anaplastic lymphoma kinase (ALK): A potential oncogenic driver in triple-negative breast cancer?
Authors: Sachdev Jasgit C. , Naini Pranitha , Arteta-Bulos Rafael , Vontela Namratha , Hout David Richard , Hirsch Fred R. , Morris Stephan , Osarogiagbon Raymond U. 
Published: March 2020

1067 Background: TNBC, a molecularly heterogeneous subset of breast cancer, has an aggressive clinical course and no established targets for therapy. Wild-type ALK gene amplification by fluorescence in situ hybridization (FISH) was noted in 6/9 inflammatory TNBC specimens (Robertson et al. SABCS, P3-01-18). The status of ALK, full-length or fused, in non-inflammatory TNBC has not been described. Identification of a biomarker such as ALK in TNBC would be clinically significant, given the ongoing development of multiple ALK inhibitors. We screened for ALK expression in TNBC specimens with a novel patented qRT-PCR assay (Insight ALK Screen). Methods: We tested archived formalin-fixed, paraffin-embedded blocks of TNBC tissue. Evaluable specimens had sufficient tumor material for 10 slides with 5-micron sections. Insight ALK Screen was performed using previously described methodology (Hout, et al. AACR 2011, Abstract 2220). We subjected ALK Screen positive specimens to ALK break-apart FISH (Vysis) and direct sequencing analysis. Results: See clinical characteristics (Table). Insufficient RNA: 8/40 (20%). Insight ALK Screen-positive: 8/32 (25%). Break-apart FISH performed on these 8 specimens suggested 3/8 to be positive for ALK translocation and 2/8 to contain amplification of ALK without a translocation. The ALK-amplified specimens were subsequently confirmed with sequencing of RNA-PCR products to express full-length ALK. One additional ALK Screen-positive, FISH-negative specimen had full-length ALK expression confirmed on sequencing. Further analysis of the other 2 ALK Screen-positive cases is pending. Conclusions: ALK expression was seen in ~25% of TNBC specimens screened by Insight ALK Screen. We observed both ALK translocations and amplification/overexpression of full-length ALK. We are testing additional specimens by FISH and immunohistochemistry to evaluate the full spectrum of ALK alterations in TNBC. Updated data will be presented. [Table: see text]
Sixteen years follow-up results of a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer.
Authors: Zwenger Ariel Osvaldo , Leone Julieta , Vallejo Carlos Teodoro , Perez Juan Eduardo , Romero Alberto Omar , Machiavelli Mario Raul , Romero Acuna Luis , Dominguez Maria Ester , Langui Mario , Fasce Hebe Margot , Leone Bernardo Amadeo , Ortiz Eduardo , Leone Jose Pablo , Iturbe Julian 
Published: March 2020

1073 Background: Neoadjuvant chemotherapy allows direct evaluation of the tumor’s sensitivity to therapy, eradication of micrometastatic disease and the possibility of performing breast conserving surgery. The aim of this study was to describe long-term results of neoadjuvant chemotherapy in stage III breast cancer patients (pts). Methods: We evaluated 126 pts with stage III breast cancer that participated in a phase-II randomized trial of neoadjuvant 5-fluorouracil, doxorubicin and cyclophosphamide (FAC every 21 days) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF days 1 and 8 every 28). Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Response was assessed by WHO criteria. Results: Pts characteristics were well balanced in both groups (FAC: 64pts, CMF: 62pts). Median follow-up was 4.5 years (range 0.2-16.4). No significant difference was found regarding acute and long-term toxicity; however, alopecia was more frequent in FAC group. Breast conserving surgery was performed in 13.5% of pts with no difference between groups. Objective response rate (OR) was similar in both groups but pathological complete response was achieved by 4 pts who received FAC. Although both groups had similar locoregional and distant recurrences, contralateral breast cancer was higher in the CMF group (6.5% vs 1.6%, P=NS). Disease free survival (DFS) and overall survival (OS) data are shown in the table. After 16 years of follow-up, 42.1% (n=53) of pts are still alive. Disease progression was the principal cause of death in both groups (78.9% vs 84.2%). Conclusions: To the best of our knowledge, this is the first study to report long-term outcomes of FAC and CMF in the neoadjuvant setting. Within the sensitivity of our study, both regimens showed similar OR, long-term toxicity, DFS and OS rate at 16 years. Around 40% of pts are currently alive. Clinical trial information: NCT00002696. [Table: see text]
The effect of HCV serological status on doxorubicin-based chemotherapy-induced toxicity and disease-free survival in breast cancer patients.
Authors: Abd-El-Moneim Salah-Eldin , Welaya Karim Youssry , El-Assal Shaaban , Salama Ossama Eissa , Ghanem Hamdy M. 
Published: March 2020

1075 Background: Breast cancer and HCV are two frequent diseases in Egypt. There is a considerable probability of concurrent affection. This concurrence creates a subpopulation which needs special evaluation and care. Methods: To evaluate a subset of Egyptian breast cancer patients receiving doxorubicin based adjuvant chemotherapy, with HCV seropositivity (Group 2) compared to HCV seronegative patients (Group 1). 102 breast cancer patients, planned to receive Doxorubicin based adjuvant chemotherapy, at the Oncology Department, Alexandria Faculty of Medicine, were recruited since June 2009. Pretreatment evaluation included serological testing for HCV. FAC adjuvant chemotherapy was given. Results: HCV seropositivity was detected in 52 cases. Two cases in Group 2 developed toxic hepatitis and discontinued treatment and follow up. The remaining 100 patients suffered comparable toxicities, except for more frequent SGOT and SGPT elevations in Group 2. Diarrhea was more frequent in Group 2. Treatment delays and dose reductions were more frequently observed in Group 2. The 24 month disease-free survival and relapse pattern were not significantly different between the two groups. Conclusions: Patients receiving chemotherapy should undergo screening for the virus. Most patients with HCV were able to tolerate chemotherapy and continue the initial chemotherapy plan, without significant change in the toxicity profile or the natural course of their malignancy. Dose or regimen adjustments may be of help to less tolerant patients. A preemptive 10% initial Doxorubicin dose reduction might reduce the frequency of severe toxicity. The assistance of a gastroenterologist in HCV positive breast cancer patients, planned for chemotherapy is important.
Chemotherapy (CTX) treatment patterns for early-stage breast cancer (ESBC): Changing use of anthracyclines (A).
Authors: Serrurier Katherine M. , Hwang Jimmy , McGuire Joseph P. , Lichtensztajn Daphne , Griffin Ann C. , Gomez Scarlett Lin , Kurian Allison W. , Melisko Michelle E. , Rugo Hope S. 
Published: March 2020

1083 Background: Anthracyclines (A), given in sequence or combination, have been the mainstay of adjuvant CTX for ESBC. Recent molecular studies have questioned the value of A for ESBC. Trials for ESBC, presented primarily in 2005, have demonstrated similar or improved efficacy with non-anthracycline (NA) CTX. We sought to understand changing use of A for ESBC from 2000-2010 as reported in the population-based 9-county Greater Bay Area Cancer Registry (GBACR). Methods: Using the GBACR database, we recorded use of A or NA based CTX regimens in women with ESBC and no prior CTX from 2000-2010, and correlated type of CTX with tumor stage, receptor status, and age. We evaluated the use of A vs. NA (80% taxane-based) CTX from 2000-2005 and 2006-2010. Results: 16,476 patients (pts) met criteria for inclusion; 2,032 (12%) were excluded (missing information, or CTX not given). Pt characteristics were: median age 52 (range 21-94), stage I (25%), II (56%), and III (19%), 69% HR+. From 2000-2010, 83% received A; overall use of A decreased (87% to 57%), and use of NA increased (13% to 43%). The Table compares use of NA CTX during the two time periods by clinical variables. With short follow-up there was no difference in survival based on use of A vs. NACTX. Conclusions: Use of NA CTX significantly increased during 2006-2010; this trend was independent of age or receptor status and was more pronounced in earlier stage disease. The timing of this change correlated with the presentation of two phase III trials, emphasizing the impact of early data from phase III trials on treatment practice, and confirming results from a large claims database (Giordano). Potential outcome differences will be evaluated in NSABP-B49 and with longer follow-up of this cohort. This study was supported by the UCSF Cancer Registry and CPIC. [Table: see text]
Princess Margaret Cancer Centre (PMCC) Integrated Molecular Profiling in Advanced Cancers Trial (IMPACT) using genotyping and targeted next-generation sequencing (NGS).
Authors: Bedard Philippe L. , Oza Amit M. , Tsao Ming-Sound , Leighl Natasha B. , Shepherd Frances A. , Chen Eric Xueyu , Tannock Ian , Krzyzanowska Monika K. , Dhani Neesha C. , Clarke Blaise , Berman Hal K. , Serra Stefano , Craddock Kenneth J. , Chadwick Dianne , Zhang Tong , Sukhai Mahadeo A. , Yu Celeste , Hansen Aaron Richard , Kamel-Reid Suzanne , Siu Lillian L. 
Published: March 2020

11002 Background: IMPACT is an institution-wide screening program to identify patients (pts) treated at PMCC with somatic alterations that can be matched to targeted therapies. Methods: Pts with advanced breast, colorectal (CRC), non-small cell lung (NSCLC), ovarian cancers and selected other solid tumors treated at PMCC were eligible. Tumor DNA was isolated from a FFPE archived sample and genotyped using a customized Sequenom panel (23 genes, 280 mutations) in a CLIA-certified laboratory. Verified mutations were reported in pts electronic health records. Selected FFPE samples were further characterized by NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage) for platform validation. Results: From Mar 1/12-Jan 10/13, 485 pts were enrolled with median 1 prior treatment for advanced disease (range 0-6). Of 33 (7%) screen failures, 5% were for insufficient tissue and 2% for clinical deterioration. Median DNA quantity from FFPE = 4250ng (range 15-32550ng). The median time from tissue receipt to reporting was 5 weeks (range 1-23). Mutations were identified by Sequenom in 137/349 (39%) pts, including 24/79 (30%) breast, 40/80 (50%) CRC, 54/88 (61%) NSCLC, 17/78 (22%) ovarian, and 2/24 (8%) other cancers. Mutations detected were: 76 KRAS, 35 PIK3CA, 22 EGFR, 5 NRAS, 5 ERBB2, 5 CTNNB1, 4 BRAF, and 1 AKT1. MiSeq was concordant with Sequenom in 112/113 (99%) pts, with mutations identified in 94/114 (82%). The average number of mutations detected by MiSeq was 1.72/pt (range 0-7) compared with 0.49/pt by Sequenom (range 0-2). After a median follow up of 5.0 months, 31/137 (23%) pts with mutations have been matched to targeted therapies, including 14 pts enrolled in clinical trials (15 trials) matched to their genotype. Of the 10 trial pts with at least one response assessment, 3 PR (1 confirmed) and 2 SD ≥ 24 weeks have been observed. Conclusions: Molecular profiling can be integrated into the routine care of advanced cancer pts. Genotyping and targeted NGS are feasible in a clinical laboratory using stored archival FFPE tumor samples. NGS identifies additional actionable mutations to inform clinical-decision making. Clinical trial information: NCT01505400.
Development and validation of an immuno-PET tracer for patient stratification and therapy monitoring of antibody-drug conjugate therapy.
Authors: Ilovich Ohad , Natarajan Arutselvan , Sathirachinda Ataya , Kimura Richard , Srinivasan Ananth , Gebauer Mathias , Kruip Jochen , Carrez Chantal , Sassoon Ingrid , Blanc Veronique , Sarkar Susanta K. , Gambhir Sanjiv Sam 
Published: March 2020

11006 Background: SAR566658 is an antibody-drug immunoconjugate consisting of a humanized monoclonal antibody (huDS6) against the tumor-associated MUC1-sialoglycotope, CA6, conjugated to a cytotoxic maytansinoid (DM4). SAR566658 is currently undergoing phase I clinical trials in patients with CA6-positive solid tumors. A companion diagnostic based on huDS6 may facilitate patient stratification and early evaluation of therapeutic efficacy. The present study describes the development and preclinical evaluation of three novel Copper-64 (t½= 12.7h) labeled antibody fragments (two Fabs and a diabody) derived from the huDS6 antibody. One fragment was chosen based on imaging figures of merit for further specificity evaluations. Methods: The affinity of all fragments and their DOTA conjugates to CA6 was validated using flow cytometry. The DOTA conjugates were labeled with Copper-64 and evaluated in human serum stability studies, in vivo small animal PET imaging and 24-hour biodistribution studies in nude mice bearing either CA6 positive (WISH) or CA6 negative (A2780) subcutaneous tumors. The specificity of the lead tracer was evaluated in vivo via blocking studies and isotype controls. Results: All fragments and their DOTA conjugates had high affinity (Kd = 4-20 nM) for WISH cells. 64Cu-DOTA-B-Fab gave superior results in radio-synthesis (RCY - 60%, SA - 55 GBq/µmole, >99% purity), serum stability (94±5%, n=3) and biodistribution profile. Its two isotype controls gave statistically significant (P<0.05) uptake values in WISH but not A2780 tumors (see table). Blocking with B-Fab or huDS6 prior to tracer administration afforded a 23% (p<0.05, n=8) and 26% (p<0.05, n=7) decrease in WISH tumor uptake, respectively. Conclusions: These preclinical studies suggest that 64Cu-DOTA-B-Fab may be a suitable companion diagnostic for SAR566658 in cancer patients and requires further investigation.[Table: see text]
Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with acquired resistance to erlotinib.
Authors: Weissman Jonathan S. , Giannikopoulos Petros , St. John John , Uzilov Andrew V. , Costa Carlota , Karachaliou Niki , Sansano Irene , Jantus-Lewintre Eloisa , Stahel Rolf A. , Vergnenegre Alain , Gervais Radj , Perez-Gracia Jose Luis , Lozano Maria D. , Wellde Anne S. , Bordoni Rodolfo , Cardona Zorrilla Andres Felipe , Polkinghorn William Reilly , Wellde George W. , Rosell Rafael , Bivona Trever Grant ,   Cancer Therapeutics Innovation Group
Published: March 2020

11010 Background: NSCLC p with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been performed. Methods: FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 11 EGFR mutant NSCLC p. DNA was extracted from all tumor and corresponding normal tissue samples and underwent whole exome sequencing using the Illumina HiSeq2500. RNA was extracted from all tumor samples and analyzed by whole transcriptome sequencing, also using the Illumina HiSeq2500. Results: Erlotinib resistant NSCLC specimens harbored upregulation of known resistance drivers including MET and AXL and novel alterations including upregulation of genes that are: 1) recurrently mutated in NSCLC, including ALK, STK11; 2) components of established embryonic stem cell signatures, including targets of Nanog, Oct4, Sox2, c-Myc, 3) neuronal lineage specific regulators, including NTRK3, NRCAM, ALK, LRP4. The analysis also revealed downregulation of several genes that are: 1) components of innate and acquired immunity, including HLA-A, -B, DQ, CD40; 2) phosphatases regulating survival signaling pathways, including PTEN, PTPRD, 3) proapoptotic components, including BNIP3L, IKIP. Conclusions: This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC p receiving targeted therapy. We identified known and novel molecular biomarkers of erlotinib acquired resistance in NSCLC p, and uncovered a previously unappreciated role for genetic events governing stem cell and neuronal phenotypes as well as immune evasion in erlotinib acquired resistance in NSCLC p. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC p.
Real-time clinical application of next-generation sequencing (NGS): Results from a multicenter program.
Authors: Hansen Aaron Richard , Brown Andrew M. K. , Bedard Philippe L. , Hotte Sebastien J. , Winquist Eric , Goss Glenwood D. , Vergidis Dimitrios , Hirte Hal W. , Welch Stephen , Zhang Tong , Stein Lincoln D. , Ferretti Vincent , Watt Stuart , Jiao Wei , Ng Karen , Petrocelli Teresa , Siu Lillian L. , McPherson John D. , Kamel-Reid Suzanne , Dancey Janet 
Published: March 2020

11016 Background: NGS techniques enable the identification of actionable mutations in clinical tumor samples. The objective of this study is to assess feasibility and explore the impact of real-time targeted NGS on therapeutic decision-making. Methods: Patients (pts) with advanced solid tumors underwent a biopsy of a metastatic lesion. The first phase was performed with Sequenom MassARRAY somatic genotyping and Pacific Biosciences RS-targeted NGS. The second phase broadened genomic coverage in both Sequenom and Illumina MiSeq. All pts had a molecular profiling (mp) report issued after identified actionable mutations were verified by Sanger sequencing in a CLIA-lab and reviewed by an expert panel. “Actionability” was defined as having prognostic, predictive or diagnostic implications on patient management. Details of clinical outcomes and subsequent matched therapy, if applicable, were captured. Referring physicians were surveyed on the impact of mutation results on their treatment recommendations. Results: These are summarized in the Table. Conclusions: Broader mp platforms resulted in more identified actionable mutations which required a longer time for verification prior to reporting, but may yield a greater impact on clinical decision-making. However, the matching of pts to drugs based on their molecular profiles depends highly on drug access. For mp to be clinically relevant, it must be coupled with access to approved drugs or to investigational agents on clinical trials. Clinical trial information: NCT01345513. [Table: see text]