bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roles of cMET/ErbB3 activation and overexpression in the development of resistance to EGFR inhibitors in NSCLC patients.
Authors: Ahn Myung-Ju , Park Silvia , Sun Jong-Mu , Ahn Jin Seok , Park Keunchil , Langley Emma J. , Kim Phillip Sangwook , Singh Sharat , Lockton Steve 
Published: March 2020

11113 Background: Multifaceted efforts in the molecular and cellular research of lung cancer revealed many critical pathway dysregulations due genetic and epigenetic alterations to alter balances in signal transduction leading to carcinogenesis. Methods: US guided FNAs or pleural fluid were collected from 44 NSCLC patients enrolled in on-going prospective study involving EGFR inhibitors (gefitinib, erlotinib, or afatinib) and evaluated for EGFR as well as other various receptor tyrosine kinases (RTKs, i.e. ErbB2, ErbB3, cMET, IGF1R, ALK, etc) and downstream AKT and MAPK pathway proteins for their level of expression and activation in order to 1) Compare objective response rate according to the expression/activation of RTK and pathway proteins; 2) Evaluate the modulation of the RTK and pathway proteins during the treatment of EGFRi; 3) Correlate between activating EGFR gene mutations and RTK activation in patients treated with EGFRi. Results: Majority of patients over-expressed EGFR. While not overexpressed, varying and significant levels of cMET and ErbB3 were found and quantitated in each patient. A striking difference in PFS was observed with respect to relative levels of cMET to EGFR in pretreatment FNA. Regardless of EGFR mutation status, patients with higher levels of EGFR to cMET (or higher E/M-Index) showed superior PFS. With an increase in cMET involvement (or decrease in E/M-Index; continuous variable), NSCLC patients exhibited worse clinical outcome with reduction in PFS (as shown in the Table). Furthermore, patients with shorter PFS (< 8 months) had significantly higher levels of total and phosphorylated ErbB3 (67% positive) than patients with longer PFS (>8 months, 27% positive). Conclusions: This study clearly demonstrates the critical roles of cMET and ErbB3 in resistance to EGFR inhibitors in NSCLC patients. E/M-Index and activation may serve as predictive markers for treatment selection with EGFRi and cMETi, and should be validated in prospective clinical studies. [Table: see text]
Two lipids based on lipidomics as novel biomarkers for early detection of squamous cell lung cancer.
Authors: Deng Youping , Ai Junmei , Borgia Jeffrey Allen , Chen Hankui , Mahon Brett , Liptay Michael J. , Bonomi Philip , Mulshine James L. 
Published: March 2020

11114 Background: Lipids play roles in membrane structure, energy storage, and signal transduction as well as lung cancer. Lipidomics, a new technology aims to measure all the lipids in a cell, has not been applied to diagnostic test development for a variety of cancer types. Here, we adopt lipidomics as a means to identify plasma lipid markers for the early detection of lung cancer and complement CT-based methods for lung cancer screening. Methods: Using mass spectrometry, we profiled 390 individual lipids in a training discovery cohort comprised of cohorts that were either at “high-risk” for lung cancer (n=22) and squamous cell carcinoma at early stages (n=22). Cases had a minimum of two years clinical follow-up and were matched in terms of race, sex, age and smoking status. Gain ratio feature selection and local weighted classification model were employed to find the best training classifier, which was further validated against an additional cohort, including high-risk individuals (n= 20) and squamous cell carcinoma patients (n=17). Results: In the training discovery stage, we found 20 distinct lipids that were significantly distributed between high-risk and cases of squamous cell carcinoma. We further defined a two lipid marker panel had a training accuracy at 95.5% sensitivity, 90.9% specificity and 95.2% AUC (Area under ROC curve). The validation accuracy against the additional cohort is 100.0% sensitivity, 90.0% specificity and 99.0% AUC (Table). The power for sample size we used in both discovery training and validation stages were over 90%. Conclusions: Using lipidomics we identified two lipid markers capable of discerning cases of squamous cell carcinoma from individuals at high risk for lung cancer, with a high sensitivity, specificity and accuracy. The markers maybe further developed as a quick, safe blood test for early diagnosis of squamous cell lung cancer and reduce unnecessary follow-up imaging or invasive procedures. [Table: see text]
Analysis of prognostic factors after 16 years of follow-up in a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer.
Authors: Leone Julieta , Leone Jose Pablo , 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 , Iturbe Julian , Zwenger Ariel Osvaldo 
Published: March 2020

11118 Background: Neoadjuvant chemotherapy is a standard treatment in stage III breast cancer. Prognostic factors can help to identify patients (pts) with high risk of recurrence. The aim of this study was to assess several prognostic factors after a long follow-up, in stage III breast cancer pts, treated with neoadjuvant chemotherapy. 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: The median age was 52 years (range 24-75). Median follow-up was 4.5 years (range 0.2-16.4), disease free survival (DFS) 4.8 years and overall survival (OS) 6.4 years. Results of the phase-II study showed no difference in efficacy between groups. Univariate analysis showed that the number of pathologically involved lymph nodes (pLN), pathologic response and estrogen and progesterone receptor status correlated with DFS and OS. Number of pLN was the only prognostic factor with statistical significance in Cox regression test for both, DFS and OS (P=0.0004 and P=0.0006, respectively). In a subgroup analysis of pts with pLN, we found no difference in survival when we compared FAC with CMF. Conclusions: The prolonged follow-up of this study provides a unique opportunity to evaluate factors that predict long-term outcomes. After 16 years of follow-up, the number of pLN remains the most powerful predictor of survival. The subset of pts with pLN had similar survival regardless of the regimen used. Clinical trial information: NCT00002696.
Meta-analysis to determine the clinical effectiveness of axillary lymph node dissection in the treatment of operable primary breast cancer.
Authors: Joyce Doireann , Manning Aidan , Hill Arnold D. , Kell Malcolm R. , Barry Mitchel 
Published: March 2020

1112 Background: The optimum surgical management of the axilla is controversial. Guidelines mandate axillary surgery in the setting of positive sentinel nodes. However, recent studies have questioned the oncological benefits of this potentially morbid procedure. Therefore a meta-analysis of relevant randomised trials was performed to clarify this issue. Methods: A comprehensive search of published randomized trials that compared patients with primary operable breast cancer with/without axillary lymph node dissection (ALND) was performed using MEDLINE and available data was cross referenced. Reviews of each study were conducted, and data were extracted. Primary outcomes were overall survival and recurrent axillary disease. Results: A total of 4,759 patients with operable primary breast cancer were identified from 13 randomised controlled trials comparing patients with/without ALND. Overall survival favours patients not having ALND (OR = 1.38 (95% CI = 1.12 TO 1.69, p=0.002)) however patients undergoing ALND had similar disease free survival (OR=1.04 (95% CI= 083-1.31, p=0.7). However, though axillary recurrence was uncommon it was significantly less so following ALND (1% vs. 5 %, p<0.05, ALND vs. No ALND). Conclusions: Based on this meta-analysis, ALND does not appear to positively impact on breast cancer survival. Enhanced and targeted adjuvant treatment strategies may facilitate less aggressive axillary surgery. The management and implications of a positive sentinel node need to be re-evaluated in this regard.
TARGIT-A trial: Updated results for local recurrence and survival for the German centers.
Authors: Wenz Frederik K. , Vaidya Jayant S. , Bulsara Max , Suetterlin Marc , Sperk Elena , Ataseven Beyhan , Pigorsch Steffi , Feyer Petra C. , Blohmer Jens U. , Kaufmann Manfred , Roedel Claus , Friese Klaus , Belka Claus , Solomayer Erich , Fleckenstein Jochen , Park-Simon Tjoung-Won , Bremer Michael , Joseph David John , Tobias Jeffrey S. , Baum Michael 
Published: March 2020

1121 Background: In 2010, we reported data on local control and early toxicity for the TARGIT-A trial of intraoperative radiotherapy after lumpectomy for early breast cancer. The updated results and first analysis of survival of the whole cohort (n = 3,451) were presented at San Antonio Breast Cancer Symposium in December 2012. We analysed the German cohort of patients, which was supposed to be more homogeneous (prepathology IORT only, homogeneous treatment in EBRT arm) and lower risk (older, smaller tumors, larger margin) than the international cohort of patients due to legal restrictions for radiotherapy studies in Germany. Methods: TARGIT-A was a randomised trial in patients >=50 years with invasive ductal carcinoma (<= 2cm) undergoing breast conserving surgery comparing standard fractionated whole breast EBRT (56 Gy) with single dose TARGIT (20 Gy) immediately after tumor excision / at the time of the primary operation. The experimental arm mandated additional EBRT (46 Gy, excluding a boost, n = 126) if adverse features were detected on final pathology (EIC, N+, margin < 1 cm) making this a “risk-adapted policy”. Median follow-up was 2 years and 5 months. Results: 734 patients recruited from 7 centres in Germany. Patient’s ages were <=50y 3%, 51-60y 33%, 61-70y 51%, >70y 12%. Tumour sizes were 0-1cm 35%, 1.1-2cm 55% and >2cm 11%. Grade I 29%, II 59%, III 12% and nodes negative 81%, 1-3 nodes 16%, >3 nodes 3%. At 5-years, the absolute number of events in TARGIT vs. EBRT were as follows: Primary outcome: IBR 4 vs. 1, Exploratory outcome: All recurrences (breast +axilla+contralateral+distant recurrence) 11 vs. 7, Secondary outcome: All deaths 6 vs. 12, Breast Cancer deaths 3 vs. 5, Non-Breast Cancer deaths 3 vs. 7. Conclusions: Patients in the TARGIT-A trial have excellent 5 year outcomes (local control > 97%, overall survival >= 94%) in both arms of the trial. Clinical trial information: protocol 99PRT/47.
Propensity-score matched pair comparison of accelerated partial breast irradiation (APBI) and whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS).
Authors: Wilkinson John Ben , Fowler Ashley , Marina Ovidiu , Wallace Michelle , Marvin Kimberly , Grills Inga S. , Brabbins Donald S. , Chen Peter Y 
Published: March 2020

1123 Background: DCIS remains a cautionary criterion for APBI by the ASTRO APBI consensus statement. We performed a matched analysis to compare the efficacy of WBI and APBI for patients with DCIS. Methods: Women with DCIS treated with APBI or WBI were reviewed. APBI (n=102) patients with ≥2 y follow-up were matched 1:3 to WBI (n=546) patients with ≥5 y follow-up by age, tumor size, nuclear grade, ER status, margin status, and laterality. Ipsilateral breast tumor recurrence (IBTR), distant metastasis (DM), contralateral breast cancer (CLBC) and cause-specific survival (CSS) were compared by cumulative incidence (Gray’s) and competing risks regression (Fine and Gray’s), and overall survival (OS) and disease-free survival (DFS) by Kaplan-Meier (log-rank test). Results: Median follow-up was 4.6 y (2.0-14.7) for APBI and 9.0 y (5.4-27.0) for WBI. Median (range) or percentages are shown (Table). Patients did not differ by match criteria. There were 17 LR, 1 DM, 19 CLBC, 2 CSS, 22 OS, and 19 DFS events during follow-up. The patient groups had similar rates of cancer-related events including ipsilateral and contralateral breast recurrences at both five and eight years. Treatment type, age, tumor size, nuclear grade, ER status, and hormone therapy (HT) were not prognostic of LR or CLBC on uni- and multi-variate analyses. Conclusions: APBI provides equivalent and exemplary outcomes compared to WBI following breast-conserving surgery for DCIS. These findings support previous reports on the efficacy of APBI in the treatment of noninvasive breast carcinoma. Prospective randomized comparison of APBI to WBI for DCIS is needed. [Table: see text]
PTEN-deficient breast cancer in neoadjuvant treatment.
Authors: de la Haba-Rodriguez Juan , M Cano , Y Rangal , Cristina Morales , E Fuentes , M Montero , I Porras , B Chia , A Rodriguez , Aranda Enrique 
Published: March 2020

1125 Background: Loss of function mutations in the tumour suppressor gene PTEN or lack of PTEN expression have both been observed in a wide range of human tumours. PTEN encodes a phosphatase, whose activity antagonizes PI3 kinase signal pathway by dephosphorylation the plasma membrane lipid, phosphoinositide-3,4,5-trisphosphate (PIP3). Loss of PTEN phosphatase activity is thought to foster tumorigenesis, at least in part, by causing downstream constitutive activation of AKT. In addition to this role, PTEN has been suggested to have a nuclear function in maintaining genomic stability[2]. Our proposal is to identify those tumours without expression of PTEN, their characteristics and response to treatment. Methods: We have studied PTEN expression by immunohistochemistry in tumours samples from 86 patients treated with neoadjuvant treatment. Normal breast epithelium or vascular endothelium were used as positive control. PTEN was evaluated by inmunoreactive stain score, taking into account staining intensity and percentage of positive cells, PTEN deficiency (PTEN -) has been stablished by a IRS=0[1]. We analyzed the PTEN localization (nuclear vs citoplasmatic). Results: In our serie, 38 (44.2%) of the tumours samples were PTEN deficient. Taking into account as reference PTEN + tumours, we have found that PTEN deficient tumours are more frequently; ductal carcinoma (94.2% vs 81.8%), G3 (72% vs 48.7%), ER negative (47% vs 30.4%), Triple negative (24.2% vs 15%) and higher Ki67 expression (>20%) in the 100% of PTEN deficient tumours. The pathological rate response was PTEN -:18.4% vs PTEN +:19.1% p:ns, and the recurrence rate was higher in PTEN- (26,3% vs 8,3%) p:0.025. Conclusions: The PTEN deficient breast tumours is associated to more histological aggressive profile, and we have not found relations with the pathological rate response to neoadjuvant treatment.
Referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: A nationwide study based on 240,134 consultations and 134,652 genetic tests.
Authors: Pujol Pascal , Stoppa-Lyonnet Dominique , Frébourg Thierry , Blin Julien , Picot Marie Christine , Lasset Christine , Bonaiti Catherine , Berthet Pascaline , Grandjouan Sophie , Soubrier Florent , Buecher Bruno , Guimbaud Rosine , Lidereau Rosette , Jonveaux Philippe , Olschwang Sylviane , Houdoyer Claude , Bressac Brigitte , Galibert Virginie , Nowak Frederique , Nogues Catherine 
Published: March 2020

1528 Background: Patients referral to dedicated consultations for cancer predisposition syndrome has become a standard in clinical practice. Based on nationwide data from the French national cancer institute (NCI), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with a BRCA1/2 or MMR mutation. Methods: All French cancer genetics centres completed annually a survey collecting standardized parameters for the NCI from 2003 to 2011. We report on the analysis of a total of 240,134 consultations and 134,652 genetic tests that enabled to identify 32,494 mutation carriers. Results: From 2003 to 2011, 141,639 (59 %) and 55,698 (23.2 %) patients were referred for a breast or a colorectal cancer predisposition syndrome, respectively. During this period, we found a dramatic and steadily increase in genetic tests performed for the BRCA1/2 genes (from 2095 to 7393 tests/year, P<0.0001) but not for the MMR genes (from 1144 to 1635/year, P=NS). The percentage of deleterious mutations identified in the probands tested was 13.8 % and 20.9 % in BRCA1/2 and Lynch syndromes, respectively. In families with a BRCA1/2 or a MMR identified mutation, there was an average number of 3.03 relatives performing target tested. Conclusions: This nationwide study shows a lack of referral and genetic testing in Lynch syndrome as compared to BRCA1/2 syndrome. Only a third of relatives for a proband identified with a BRCA1/2 or MMR gene mutations performed a genetic targeted test. Enhanced information about validated benefit of genetic testing should be given to clinicians and patients particularly for Lynch syndrome and for relatives of a proband carrying an identified BRCA1/2 or MMR genes mutation.
PROFILE: Broadly based genomic testing for all patients at a major cancer center.
Authors: Rollins Barrett J , MacConaill Laura E. , Wagle Nikhil , Garcia Elizabeth , Kuo Frank C , Longtine Janina A , Garber Judy Ellen , Janeway Katherine A. , Fuchs Charles S. , Bertagnolli Monica M. , Soiffer Robert , Matulonis Ursula , Lin Nancy U. , Hahn William C , Garraway Levi A. , Kantoff Philip W. , Lindeman Neal Ian 
Published: March 2020

1531 Background: Genotyping plays an increasingly important role in the management of cancer patients. However, the landscape of genomic abnormalities is unknown for many cancers and the influence of specific genotypes on clinical behavior is often unclear. To address these deficiencies, we developed PROFILE, a project designed to obtain genomic information on all patients who come to our hospitals for cancer-related care. Methods: Clinically acquired specimens were genotyped using a mass spectrometry genotyping test (OncoMap) which assays 471 alleles in 41 cancer-related genes. Because the majority of these alleles currently have no known clinical meaning, we implemented PROFILE as a research test. This required developing an "umbrella" protocol governing PROFILE activity, a highly simplified 2-page consenting brochure, and a centralized consenting process. We created process flows for retrieving clinical specimens and performing OncoMap in a CLIA-certified laboratory. We return results on individual participants to their ordering providers who can use actionable findings to guide management. All results are stored in a database which can be queried using a web-based search tool that returns aggregate results. Approval to link specimen to clinical information can be sought by a streamlined process of User Committee and IRB approval, and linkage is performed by IS acting as honest brokers. Results: From August 2011 through December 2012, we consented 12,980 patients (consent rate >70%). We found that 39% of clinical samples are of sufficient quality to yield OncoMap results. We have reported and stored 3,000 genotyping results. OncoMap mutations were detected in 40% of clinical samples. As expected, mutations in KRAS, PIK3CA, TP53, and BRAF were most commonly observed across all tumor types. However, rarer mutations were also detected in RET, PIK3R1, and ERBB2 among others. Conclusions: Novel operational approaches have permitted enterprise-wide, broadly-based genotyping that serves a combination of research and clinical needs. Early insights from this database will be discussed along with information about their impact on clinical management.
Telomere length and recurrence risk after curative resection in women with adenocarcinoma of the lung: A prospective cohort study.
Authors: Kim Eric S. , Ye Yuanqing , Vaporciyan Ara A. , Xing Jinliang , Huang Maosheng , Gu Jian , Roth Jack A. , Lippman Scott Michael , Wu Xifeng 
Published: March 2020

1532 Background: We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small cell lung cancer (NSCLC). Methods: This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative resection at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time PCR. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Results: Median duration of follow-up was 61 months and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared to those without recurrence (1.13 vs 1.07, P=0.046). A subgroup analysis indicates that women had longer RTL compared to males (1.12 vs 1.06, P=0.025), and the patients with adenocarcinoma demonstrated longer RTL compared to those with other histologic types (1.11 vs 1.05, P=0.042). To determine if longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, gender, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR=2.25; 95% CI, 1.02-4.96, P=0.044) and adenocarcinoma subgroups (HR=2.19; 95% CI, 1.05-4.55, P=0.036). The increased risk of recurrence due to long RTL was more apparent in females with adenocarcinoma (HR=2.67; 95% CI, 1.19-6.03, P=0.018). Conclusions: This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma appear to be special subgroups in which telomere biology may play an important role. (Supported by NCI CA 111646, CA 55769, and CA 70907.)