bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of a family history of cancer with risk of relapse and death in pediatric cancer patients
Authors: Eichstadt S. L. , Dahl G. V. , Fisher P. G. , Ford J. M. , Schiffman J. D. 
Published: August 2020

10029 Background: The association between family history of cancer (FHC) and outcome remains uncertain. Relapse and survival of children with FHC has not been well studied. Such information would be valuable for prognosis, refining treatment protocols, and long-term follow-up in pediatric patients with FHC. Methods: An historical cohort study of all pediatric patients diagnosed with cancer at Lucile Packard Children's Hospital at Stanford from 1999 - 2002 was performed (n = 363, mean age: 8.4 yrs [0–28 yrs]). FHC among 1st, 2nd and 3rd degree relatives was obtained from the first 10 consecutive encounters in the electronic medical record. Relapse, secondary malignancy, and survival data were also acquired. The relative risks for these endpoints were calculated between patients with FHC among 1st and/or 2nd degree relatives and those with negative FHC. Patients without documented FHC were excluded (n = 100). Results: 108 (41%) newly diagnosed pediatric patients had reported FHC (1st Degree: n = 14 [5%], 2nd Degree: n = 58 [22%], 3rd Degree: n = 36 [14%]). Patients with reported FHC among 1st and/or 2nd degree relatives were at increased relative risk [RR] for relapse (1.96, 95% confidence interval [CI] 1.27–3.02) compared to patients with negative FHC (n = 191). In particular, patients with Hodgkin Disease (HD) and FHC (n = 12) were more likely to relapse (RR 1.79, 95% CI 1.19–2.72) and at increased risk of death (RR 1.72, 95% CI 1.18–2.53), compared to HD with negative FHC (n = 8). Similarly, patients diagnosed with ALL and FHC (n = 22) had increased risk of death (RR 2.25, 95% CI 1.06–4.8) compared to ALL patients with negative FHC (n = 56). For patients diagnosed with any pediatric cancer and positive FHC in 1st degree relative, RR of death was significantly elevated (3.74, 95% CI 1.20–11.70). Conclusions: Pediatric cancer patients with positive FHC among 1st and/or 2nd degree relatives appear to have higher relative risk of relapse compared to those with negative FHC. Additionally, an increased risk of death was associated with HD and ALL patients with positive FHC. Patients with 1st degree relative with malignancy had an increased risk for death compared to those without cancer among 1st degree relatives. These findings may reflect underlying genetic predispositions in children which contribute to outcome. No significant financial relationships to disclose.
Developing a prediction model for benefit from fulvestrant in heavily pretreated metastatic breast cancer (MBC) patients
Authors: Amir E. , Freedman O. C. , Dranitsaris G. , Napolskikh J. , Chia S. , Petrella T. , Dent S. , Kumar R. , Fralick M. , Clemons M. 
Published: August 2020

1041 Background: Fulvestrant use in heavily pretreated patients with MBC is associated with highly variable responses. This study aimed to characterize the benefit of fulvestrant therapy and develop a prediction model for clinical benefit in this setting. Methods: A nationwide, retrospective chart review of patients enrolled in a Canadian compassionate use program was performed. This program mandated prior therapy with tamoxifen and both steroidal and non-steroidal aromatase inhibitors. Charts from the seven highest accruing centers were reviewed. Sample size was based on the derivation of a model to predict the probability of a patient remaining on fulvestrant and free from chemotherapy for at least 3 months. Results: 305 women received at least one dose of fulvestrant; 207 went on to receive chemotherapy (68%). Of these, 48 (23%) required chemotherapy at 3 months, 113 (55%) at 6 months, and 170 (82%) by 12 months. Median duration of fulvestrant treatment was 126 days (range 23–1920). Median overall survival from start of fulvestrant was 698 days (25th percentile 316 days-75th percentile 1,359 days). The preliminary prediction model showed that older age (OR 0.96, 95% CI 0.93–0.99) and having received no adjuvant hormonal therapy (OR 0.5, 95% CI 0.2–1.25) predicted a greater chance of remaining chemotherapy-free at 3 months. Presence of lung (OR 2.55, 95% CI 1.1–5.9) or brain metastases (OR12.8, 95% CI 4.1–55.4) predicted a lower chance of remaining chemotherapy-free at 3 months. Conclusions: Older age and having received no prior adjuvant hormonal therapy predicted a greater chance of remaining chemotherapy free at 3 months, while lung and brain metastases predicted a lower chance. These factors will be validated in an international data set, and may be considered when prescribing fulvestrant. A 6-month prediction model is currently under development. [Table: see text]
Effect of estrogen receptor-positive progenitor cells on a tamoxifen resistance phenotype in breast cancer cells
Authors: Selever J. , Barone I. , Lewis M. T. , Corona-Rodriguez A. , Tsimelzon A. , Di Pietro A. , Boumemdjel A. , Fuqua S. 
Published: August 2020

1042 Background: The antiestrogen tamoxifen and aromatase inhibitors are the most frequently prescribed hormonal agents for the treatment of estrogen receptor (ER) α-positive breast cancer. An important question is whether there is a group of hormone resistant, ERα-positive patients who may derive additional benefit from the addition of chemotherapy to endocrine therapy, or who may be candidates for “targeted” biologics. Dicer1 is an RNase III-containing enzyme that processes microRNA precursors into mature microRNA, which have been implicated in breast tumor invasion and metastasis. BCRP1 is a transmembrane transport protein known to efflux a number of chemotherapeutic agents, but also steroid hormones. In the present study, we investigated whether Dicer might affect response to tamoxifen in breast cancer cells, and generated estrogen receptor-positive MCF-7 human breast cancer cells stably overexpressing Dicer1, and they exhibited elevated BCRP1 protein. Methods: We utilized preclinical approaches to study the function of BCRP1 in Dicer-overexpressing breast cancer cells using in vitro growth assays in soft agar, mammosphere formation assays, and in vivo tumor initiation. Results: Microarray analyses of human breast tumors, suggested that Dicer overexpression was associated with tamoxifen resistance. Dicer-overexpressing MCF-7 cells express elevated levels of BCRP1, ALDH, and cErbB2/HER-2 evident by immunoblot analysis. The Dicer1-overexpressing cells formed soft agar colonies in the presence of tamoxifen, however Fumitremorgin C (FTC) or MBLI-97, both BCRP inhibitors, reversed resistance, and sensitized cells to tamoxifen therapy. Preclinical in vivo tumor xenograft experiments confirmed the tamoxifen-resistant phenotype. Mammosphere potential was enhanced in Dicer-overexpressing cells suggesting an enrichment of stem-like breast cancer cells. Conclusions: Our results suggest that Dicer-overexpressing breast cancer cells are a novel preclinical model for an estrogen receptor-positive breast cancer progenitor phenotype and tamoxifen resistance. Based on our data Dicer1 is a potential predictive biomarker in breast cancer, and predicts that clinical BCRP1 inhibition may facilitate tumor sensitization to hormonal therapy. No significant financial relationships to disclose.
Evaluation of the antitumor activity of sunitinib malate (SM) in solitary fibrous tumor (SFT)
Authors: Casali P. G. , Stacchiotti S. , Palassini E. , Marrari A. , Negri T. , Morosi C. , Messina A. , Pastorino U. , Gronchi A. , Pilotti S. 
Published: August 2020

10571 Background: SFT is a rare soft tissue tumor, with an unpredictable metastatic potential. When medical therapy is needed, cytotoxic chemotherapy is poorly active in this sarcoma subtype, but the activity of bevacizumab + temozolomide was recently reported. We explored the activity of SM in SFT, given the vascular pattern of this tumor and our preliminary observations about RTK activation (with upregulation of the PDGFR family, VEGFR and EGFR). Methods: From April 2008, 5 patients with progressive metastatic SFT resistant to conventional chemotherapy (male/female: 3/2 - mean-age: 58 years - PS: 0–3 - site: peritoneum 3, pleura 1, bladder 1) have been treated with continuous-dosing SM 37.5 mg/day, on an individual use basis. All patients were evaluated for response at least once, while 2 more patients are now starting therapy. RTK biochemical analysis was performed in 3 patients of this series, in addition to a group of other patients with malignant SFT whose cryopreserved material was available. Results: Between 3 weeks and 3 months, 4 in 5 patients had a tumor response according to Choi's criteria (all with RECIST stable disease) . The other patient stopped therapy for progression after 3 weeks and died 2 weeks later. Baseline PET was negative in 4 out of 5 patients. One responsive patient stopped therapy after 3 weeks for side effects and depression. The remaining 3 responsive patients are currently on treatment, although one had a focal progression after 9 months. In two, surgery of residual disease is planned, and downstream RTK signaling analysis will be performed on the specimen. Conclusions: SM has antitumor activity in SFT. This might help address an unmet clinical need in a rare sarcoma subtype. Biomolecular assessments are ongoing. [Table: see text]
Detection of local recurrences of limb soft-tissue sarcomas: Is magnetic resonance imaging (MRI) relevant?
Authors: Ferron G. , Aziza R. , Delannes M. , Filleron T. , Marquès B. , Labarre D. , Labarre D. , Chevreau C. 
Published: August 2020

10582 Background: The role of systematic magnetic resonance imaging (MRI) surveillance after resection of soft-tissue sarcomas (STS) of the limb is opened to debate. The aim of our study was to retrospectively evaluate the effectiveness of a MRI surveillance schedule performed in adult patients. Methods: 124 adult patients have been treated from 1996 to 2006 for a non-metastatic limb STS at our centre: 86 patients (70%) had clear resection margins (R0) and 111 patients (90%) received an adjuvant radiotherapy. 663 MRI examinations were performed, with a median of 5 per patient [range: 1 to 5]. The rythm of surveillance schedule was respected in 57% of the examinations. Results: Forty-one patients (33%) prematurely withdrew from the planned radiological surveillance due to metastasis diagnosis (15 cases), 5-year remission duration (5 cases), other reasons (12 cases), and drop out (9 cases). Among the 11 local recurrences (9%) which were observed, MRI was able to detect only 2 asymptomatic local recurrences, 1 with and 1 without synchronous metastasis, both had microscopically involved margins (R1). In contrast, MRI showed 11 false-positive cases. As the predictive positive value of MRI was 42%, clinical surveillance seems to be more effective. The evaluation of the cost of the systematic MRI surveillance is 200,000 euros. Clinical examination failed in 2 cases (2 asymptomatic local recurrences detected by MRI) as did MRI surveillance (2 false negative cases). In our study, cost-effectiveness was better with clinical examination than MRI surveillance. Conclusions: As observed in our study, systematic MRI surveillance is not relevant for the follow-up of all limb soft-tissue sarcomas. A prospective study could be promoted to evaluate the MRI surveillance of patient at high risk of local recurrence. No significant financial relationships to disclose.
Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma
Authors: Stevenson M. M. , Mostertz W. , Acharya C. , Walters K. , Barry W. , Tuchman S. , Ready N. , Onaitis M. , Crawford J. , Potti A. 
Published: August 2020

11001 Background: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities between normal/embryonic stem cells and mature tumor cells, specific to lung cancer, are a result of underlying biologic processes, such as specific molecular pathways and regulatory networks. Methods: Using a large cohort of lung cancer cell lines with associated gene expression data, genes associated with an embryonic stem cell identity were used to develop a ‘signature’ representative of embryonic stemness (ES) activity specific to lung adenocarcinoma. Differential biology was evaluated using Gene Set Enrichment Analysis (GSEA) and signatures of oncogenic pathway deregulation. The ES signature was applied to three independent early (stage I - IIIa) lung adenocarcinoma data sets (N = 634) with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin sensitivity was also evaluated. Results: Using Bayesian regression analysis, a 100 gene signature representative of ES activity in lung adenocarcinoma was developed and validated in a leave-one-out-analysis. GSEA identified gene sets significantly represented in the ES signature: signature of neoplastic transformation, signature of undifferentiated cancer, BRCA pathway, and fibroblast serum response pathway, all associated with cancer invasiveness. Adenocarcinomas with ES demonstrated increased activation of RAS (p = 0.0002), MYC (p = 0.0057), wound healing (angiogenesis) (p < 0.0001), chromosomal instability (p < 0.0001), and invasiveness (p < 0.0001) gene signatures. Adenocarcinomas (N= 634) with ES had a decreased survival (p<0.04). The ES signature was not prognostic in prostate, ovarian, or breast adenocarcinomas. Lung tumors (N=634) and adenocarcinoma cell lines (N=31) with ES were more resistant to cisplatin (p<0.0001 and p=0.0063, respectively). Conclusions: Lung adenocarcinomas that share a common gene expression pattern with normal stem cells were associated with decreased survival and increased likelihood of resistance to cisplatin, indicating the aggressiveness of lung tumors with a stem cell phenotype. No significant financial relationships to disclose.
IKZF1 (IKAROS) deletions as a prognostic marker in BCR-ABL1 positive acute lymphoblastic leukemia patients: A GIMEMA ALL WP Report
Authors: Iacobucci I. , Storlazzi C. , Lonetti A. , Ferrari A. , Messina M. , Cilloni D. , Papayannidis C. , Baccarani M. , Foà R. , Martinelli G. 
Published: August 2020

11005 Expression of BCR-ABL1 in hematopoietic stem cells can alone induce a chronic myeloid leukemia (CML) but cooperating oncogenic lesions are required for the generation of a blastic leukemia. To identify oncogenic sub-microscopic lesions that cooperate with BCR-ABL1 to induce ALL, by high resolution single nucleotide polymorphism (SNP) arrays (250K NspI and SNP 6.0, Affymetrix) we studied 106 patients (pts) with de novo adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (68/106, 64%), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. We characterized and mapped all breakpoints in IKZF1 gene to recognize that two major deletions occur: the first one characterized by loss of exons 4–7 (44%) and due to breakpoints in introns 3 and 7; the second one characterized by removal of exons 2–7 (19%) and due to a variable pattern of breakpoints in introns 1 and 7. In two pts we had both Δ2–7 and Δ4–7 deletions and in one we identified a deletion of all IKZF1 gene and part of GRB10. A variable number of nucleotides (patient-specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. Gene expression profiling analysis of pts with IKZF1 deletion vs wild-type pts identified a unique signature characterized by a down-regulation of genes involved in pre-B-cell differentiation (e.g. VPREB1, VPREB3, IGLL3, BLK), demonstrating that genomic IKZF1 alterations have a strong impact on trascriptoma and contribute to an impaired B-cell differentiation. Univariate analysis showed that the IKZF1 deletion is a negative prognostic marker influencing the cumulative incidence of relapse (10.1 months for pts with deletion vs 56.1 months for wild-type pts, p=0.0103) and disease-free survival (DFS) (10.1 months vs 32.1 months, respectively, p=0.0229). The negative prognostic impact of the IKZF1 deletion on DFS was also confirmed by multivariate analysis (p=0.0445). In conclusion, deletion of IKZF1 is an important event in the development of BCR-ABL1 B-progenitor ALL which significantly influences clinical outcome. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus. No significant financial relationships to disclose.
Mechanistic evaluation of the combination effect of paclitaxel (Pac) and bevacizumab (Bev) in breast cancer xenografts
Authors: Alvarez R. H. , Valero V. , Bassett R. L. , Lu C. , Dallas N. , Kiriakova G. , Bankson J. A. , Madden T. L. , Hortobagyi G. N. , Price J. E. 
Published: August 2020

11007 Background: Chemosensitization is the ability to augment the effects of standard chemotherapy. One of the possible mechanisms for chemosensitization is improving intratumoral chemotherapy concentrations by increasing total or regional delivery of chemotherapy to the tumor. This mechanism potentially leads to a decreased tumor interstitial fluid pressure (IFP). This study evaluates the interaction between tumor IFP, intra-tumor drug accumulation and blood vessel perfusion. Methods: GILM2 human breast cancer (triple negative phenotype) cells were injected into the mammary fat pad of female nude mice. Mice were randomized to 4 arms: Control, Pac 24 mg/Kg, Bev 10 mg/Kg, and the same dose for the combination Pac + Bev, twice a week for 3 weeks. Tumor IFP was assessed using an ultraminiature catheter-tip technique (Ozerdem 2005). Concentration of Pac in tumor tissue was measured using liquid chromatography mass spectrometry (LC/MS) and blood vessel perfusion was assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Ultrastructural morphology changes were assessed by electron microscopy (EM). Results: Treatment started 35 days after implantation; tumor tissue concentration of Pac was significantly increased when combined with Bev (P = 0.03). In mice treated with the combination of Pac + Bev, IFP values decreased more gradually, with sustained and significant reduction at the end of the treatment (P = 0.0068; mean SEM day 0: 28,44 ± 6,1; mean SEM day 21: 7,41 ± 2,0). The IFP changes in the other 3 experimental arms did not reach statistical significance. The combination of Pac and Bev produced substantial changes to the proportions of endothelial cell/pericytes and increased apoptosis in tumor cells by 75% (detected by immunostaining for cleaved-caspase 3). Conclusions: The combination of Pac and Bev produces significant tumor reduction and increases three-fold the concentration of Pac in the tumor. This intra-tumor augmentation of Pac was correlated with the decrease of tumor IFP, which was independent of the action of Bev alone. Results of DCE-MRI and EM analyses of the treated tumors will also be presented. No significant financial relationships to disclose.
Predictive value of novel and existing activating EGFR mutations for improved survival in malignant peritoneal mesothelioma (MPM) and response to EGFR-TK inhibitors (EGFR-TKI)
Authors: Foster J. M. , Uppala R. , Govindarajan V. , Carreau J. H. , Stan L. , Nath S. , Poonam S. , Galatica Z. , Loggie B. W. 
Published: August 2020

11030 Background: MPMs are highly aggressive tumors with most patients diagnosed surviving 8–12 months. Currently there is a paucity of information about the molecular/biological perturbations involved in tumor formation. Previously we presented (at ASCO 2007) that novel EGFR-TK mutations occurred in these tumors predictive of optimal surgical cytoreduction; but the EGFR activity of these mutations was being investigated. Here we present the EGFR activity of these mutations as well as matured outcome data. Methods: Twenty-nine MPM patients were evaluated at a single tertiary center and tumors were probed for mutations in the TK domain of EGF receptor (mut+). All specimens were examined for somatic mutations by PCR amplification and confirmed by multiple independent PCRs. Twenty-five patients were treated with cytoreductive surgery (CRS) ± IPHC and clinical data including age, sex, cytoreductive score, histology, mutation, and survival was available for comparison of the mut+ and mut- groups. A COS-7 cell expression model was used to determine the time dependent activating profile of these mutations, as well as response to EGFR-TKI-inhibitor. Results: Mutations were found in 31% (9/29) of the tumors; 7 of these mutations were novel. All 7 novel mutations and L858R mutation identified were activating mutations with similar activation profiles. All mutations were responsive to EGFR-TKI treatment. Of the 25 patients managed surgically there were 7 mut+ and 18 mut-. Two of 7 (29%) mut+ have progressed and died of disease with a MFT of 22 months; while 13/18 (72%) mut- had progressive disease and 10/18 (56%) died with median TTP and survival of 12 months and14 months respectively. Estimated 3-year PFS was 70% mut+ and 25% mut- on log rank analysis p=0.099. Conclusions: This is the first report that MPM-EGFR mutations are activating mutations and responsive to EGFR-TKI-therapy. The mut+ subset has a “relative” improved outcome compared to wild type, but still developed progressive disease. TKIs may be a promising therapy in mut+ MPMs patients. Further elucidation of other molecular and pathway perturbations in this disease is necessary, as well as, validation of these results in a larger cohort. No significant financial relationships to disclose.
Absence of the CHEK2*1100delC mutation in non-BRCA1/2 families with multiple cancer types in a high-risk clinic population of Caucasian ancestry
Authors: Gorin M. A. , Iniesta M. D. , Douglas J. A. , Milliron K. J. , Merajver S. D. 
Published: August 2020

11040 Background: Checkpoint kinase 2(CHEK2) is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. The contribution of CHEK2 mutations to familial cancer has been widely studied in breast cancer. Most notably, the CHEK2*1100delC mutation has been characterized to confer a 2-fold increased risk for breast cancer in carriers. This finding comes from studies performed on Northern and Eastern European populations. Few studies, however, have been conducted in North American. In contrast to the work done in Europe, these studies suggest a lower frequency of CHEK2*1100delC mutations in breast cancer families. The aim of this study was to determine the frequency of CHEK2*1100delC in members of breast cancer families who tested negative for a deleterious mutation in BRCA1/2. Methods: DNA sequencing was used to genotype 115 individuals for CHEK2*1100delC. Families were characterized by the presence of several cases of breast and/or ovarian cancer and multiple members with other cancers in a single lineage. Given the broad variety of cancers associated with CHEK2 mutations and its function in DNA repair, we hypothesized that these families would be enriched for harboring the CHEK2*1100delC in the germline. Results: No CHEK2*1100delC mutations were detected in 115 individuals, including 39 women diagnosed with breast cancer at an early age, 7 women with bilateral cancer, 2 men with breast cancer and 6 women with ovarian cancer, all of whom were negative for mutations in BRCA1/2.The CHEK2 Breast Cancer Consortium previously reported a frequency of 2.3% for the CHEK2*1100delC mutation among breast cancer cases from families with at least 2 cases of breast cancer (or breast and ovarian cancer) in a first- or second-degree relationship. Based on that, we had approximately 92% power to detect at least one mutation among our study cohort. Conclusions: Our data are consistent with previous reports that suggest a lower frequency of CHEK2*1100delC mutations in North American hereditary breast cancer families without BRCA1/2 mutations and enriched for multiple cancer types. The low frequency of the CHEK2*1100delC in the North American population limits its clinical relevance as a cancer predisposing gene. No significant financial relationships to disclose.