bluuebunny/crossref_metadata_2025 huggingface dataset:
Masitinib in imatinib-naive advanced gastrointestinal stromal tumor (GIST): Five-year follow-up of the French Sarcoma Group phase II trial.
Authors: Le Cesne Axel , Blay Jean-Yves , Bui Nguyen Binh , Bouche Olivier , Domont Julien , Cioffi Angela , Le Boulicaut Julie , Moussy Alain , Hermine Olivier , Adenis Antoine
Published: March 2020

10089

Background: Masitinib is a tyrosine kinase inhibitor that in vitro has greater activity and selectivity than imatinib against KIT. This multicenter, open label, phase 2 study evaluated efficacy and safety of masitinib as a first-line treatment of advanced GIST. Initial results with a median follow-up of 34 months, were previously reported in EJC 2010. We present here 5-year follow-up data from the same series with updated safety and survival data. Methods: Imatinib-naïve patients (pts) with inoperable, advanced GIST received oral masitinib (7.5 mg/kg/day) until progression, refusal or toxicity. Results: Thirty pts with a median age of 58 years (60% of males) were included from 06/2005 to 04/2007 in 5 institutions. At the cut-off date of 13/09/2011, 7/30 pts (23%) were still under treatment with median follow-up of 65 months and the median overall survival (OS) had not yet been reached (NR). The 5-year OS rate was 61.5% (95% CI [41.1;76.6]) (see Table). Among patients with confirmed KIT exon 11 mutation, 8/9 pts (89%) were still alive with one pt having died from non-treatment related causes (surgical complication) following a complete response while receiving masitinib. No additional progressions have been reported giving a total of 14 events (13 progressions and 1 death). Updated median PFS was 41.3 months (95% CI [17.5;53.8]).No additional grade 3/4 adverse events have been reported. Conclusions: Long term results of masitinib confirm an interesting activity with prolonged PFS and OS. The median PFS rate in masitinib compares very favorably to that of imatinib, which is reported as 18 months (JCO 26:626, 2008). The 5-year OS rates for masitinib in the overall and exon 11 populations also compare favorably to imatinib, both of which are reported at ≤50% for imatinib (JCO 26:626, 2008; JCO 28:1247, 2010). These results support the head to head comparison with imatinib in the currently ongoing phase 3 randomized clinical trial in first line advanced GIST pts. [Table: see text]
Doxorubicin, cisplatin, and ifosfamide (API) as first-line therapy for relapsed or metastatic uterine leiomyosarcoma.
Authors: Hadoux Julien , Rey Annie , Duvillard Pierre , Lhomme Catherine , Balleyguier Corinne , Haie Meder Christine , Morice Philippe , Gouy Sebastien , Uzan Catherine , Mazeron Renaud , Larue Christine , Pautier Patricia
Published: March 2020

10098

Background: Uterine leiomyosarcomas (ULMS) are rare gynecologic malignancies characterized by a poor prognosis due to a high rate of local and metastatic recurrences. Chemotherapy (CT) with doxorubicin or ifosfamide or both is associated with a 10 to 30% objective response rate (ORR) and a cisplatin-based multiCT approach achieved a good response rate (DECAV therapy: API + dacarbazine + vindesine, 54% ORR in uterine sarcomas), though toxic. We aimed to determine efficacy and toxicity of doxorubicin, cisplatin and ifosfamide (API) combination as first line treatment of metastatic or relapsed ULMS (MRULMS). Methods: This monocentric study included MRULMS pts with a physiological age < 65 y. CT consisted in doxorubicin 50 mg/m² d1, ifosfamide 3 g/m²/d d1d2 + mesna, cisplatin 75 mg/m² d3, + G-CSF; q 3 weeks. Results: Results in 38 pts with MRULMS were analyzed; median age was 51 (40-64), median cycles of CT was 5; 8 (21%) pts were treated for local relapse, 21 (55.3%) for metastatic disease and 9 (23.7%) for both. Metastatic sites were: lungs in 16 pts (42.1%), pelvis in 7 pts (18.4%), liver in 7 pts (18.4%), peritoneum in 6 pts (15.8%) and bone in 5 pts (13.2%); 14 pts (36.8%) had a multisite metastatic disease. Main grade 3-4 toxicities in 38 pts were neutropenia (74%), thrombopenia (60%), anemia (55%), fatigue (18%) and vomiting (13%). Febrile neutropenia was observed in 35% of pts and 1 patient died of septic shock after cycle 1. Thirty four pts were evaluable for response (4 pts had complete surgery at relapse) and 16 pts responded (4 CR + 12 PR) (ORR: 47%); 23.5% and 29.4% of the pts had respectively stable and progressive disease. For all pts (38) and evaluable pts (34), median PFS were 9.8 and 9.5 months and OS 27 and 25.3 months respectively. Conclusions: Despite toxicity observed, API is an effective treatment which compares favorably with other first line therapies for MRULMS pts.
The impact of genetic variability on severe toxicity of (neo-) adjuvant chemotherapy in breast cancer patients receiving 5-fluorouracil, epirubicin, and cyclofosfamide (FEC).
Authors: Vulsteke Christof , Lambrechts Diether , Dieudonné Anne-Sophie , Hatse Sigrid , Brouwers Barbara , Van Brussel Thomas , Neven Patrick , Belmans Ann , Schoffski Patrick , Paridaens Robert , Wildiers Hans
Published: March 2020

1020

Background: We assessed the impact of single nucleotide polymorphisms (SNP) of potential genes of interest in germline DNA on severe adverse events in breast cancer (bc) patients receiving (neo-) adjuvant FEC chemotherapy. Methods: Cases were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events. The panel of genes, genotyped using iPLEX technology on a MALDI-TOF based MassARRAY Compact Analyser (Sequenom Inc., CA, USA), included ABCBI, ABCC1, ABCC2, ABCG2, ALDH3A1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, DPYD, FGFR4, GPX4, GSTA1, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1, UGT1A1, UGT1A6 and UGT2B7. These genes are involved in the metabolization of the studied chemotherapeutics. Because of multiple testing the false discovery rate (FDR) was calculated. Results: We identified 1089 patients treated between 2000-2010 with 3-6 cycles of FEC, for whom germline DNA was available.Homozygous (TT, 0.5%) and heterozygous (GT,11%) genotypes for rs4148350 in the Multi Drug Resistance Protein I (ABCC1/MRP1), compared to wild-type (GG, 88.5%), were associated with febrile neutropenia, febrile neutropenia in first cycle, prolonged grade 4 or deep neutropenia and thrombocytopenia (80 vs 25 vs 15.7%, 40 vs 17.6 vs 9.5%, 100 vs 41.7 vs 33.8% and 20 vs 2.8 vs 0.34% respectively; p 0.0006, 0.01, 0.002 and 0.008 FDR 0.03, 0.65, 0.06 and 0.2). Variant genotypes for rs45511401 (GT/TT, 12%) in ABCC1, compared to wild-type (GG, 88%), were associated with febrile neutropenia, febrile neutropenia in first cycle and thrombocytopenia (26.5 vs 15,8%, 17.1 vs 9.7% and 3.4 vs 0.3%, respectively; p 0.007, 0.03 and 0.005, FDR 0.2, 0.75 and 0.2). Conclusions: Genetic variation in the ABCC1 gene was strongly associated with severe hematological toxicity of FEC. Other previously described SNP were not validated. This is the largest bc study in which the impact of genetic variability on the adverse events of FEC chemotherapy was investigated.
Are mastectomy rates really increasing? Experiences from a single institution and a population-based database.
Authors: Yi Min , Mittendorf Elizabeth Ann , Hwang Rosa F. , Babiera Gildy , Kuerer Henry Mark , Crow Jaime , Lange Georgia , Shah Ruchita R. , Hunt Kelly
Published: March 2020

1028

Background: Recent studies have reported increased mastectomy rates for the treatment of early stage breast cancer during the last decade. The aims of this study were to examine trends in mastectomy rates at a single institution and in a population-based database and to compare differences between the two cohorts. Methods: Patients with stage 0-II breast cancer diagnosed from 2000 to 2008 were identified from our cancer center institutional database (CC cohort, n=8,915) and the Surveillance, Epidemiology and End Results database (SEER cohort, n=359,572). Patients without primary surgery or unknown surgery type were excluded. Mastectomy rates by the year of diagnosis were evaluated and multivariable logistic regression models were built to identify clinicopathologic factors that predicted mastectomy as the treatment choice. Results: The proportion of patients treated with mastectomy decreased from 44.5% to 37.8% between 2000 and 2005 in the CC cohort (P=0.003) and from 42.8% to 36.6% in the SEER cohort (P<0.0001). Subsequently, the mastectomy rate increased to 48.6% in the CC cohort (P<0.0001) and to 40.1% in the SEER cohort by 2008 (P<0.0001). Multivariable analysis found that patients with younger age (<50), stage 0 or II cancer vs. stage I, high grade tumor, low median household income, and lobular histology were more likely to choose mastectomy in both the SEER and CC cohorts. In the CC cohort, patients with preoperative breast MRI were also more likely to undergo mastectomy. The percentages of patients receiving preoperative MRI and choosing prophylactic contralateral mastectomy increased each year in the CC cohort. The rate of preoperative breast MRI increased from 4.7% in 2005 to 9.6% in 2008 (P<0.0001). Patients choosing prophylactic contralateral mastectomy increased from 8.4% in 2005 to 11.8% in 2008 (P=0.06). Conclusions: Our study shows that there was a decrease in mastectomy rates from 2000 to 2005 and a subsequent increase in mastectomy rates from 2005-2008 in both the CC and SEER cohorts. Increased use of preoperative breast MRI and the decision to undergo contralateral prophylactic mastectomy likely contributed to the increased mastectomy rates in the CC cohort.
Short-term complications and use of breast brachytherapy in the national Medicare population in 2008-2009.
Authors: Presley Carolyn J. , Soulos Pamela R. , Herrin Jeph , Roberts Kenneth B , Yu James B. , Killelea Brigid K. , Lesnikoski Beth-Ann , Long Jessica B. , Gross Cary P.
Published: March 2020

1030

Background: Brachytherapy as an alternative to whole-breast irradiation (WBI) for early-stage breast cancer has disseminated into clinical practice; however, current national treatment patterns and associated complications remain unknown. Methods: We constructed a national sample of Medicare beneficiares aged 66 to 94 who underwent breast conserving surgery in 2008-2009 and who were treated with brachytherapy or WBI. We used hospital referral regions to assess national treatment variation and an instrumental variable analysis to compare complication rates between treatment groups, adjusting for patient and clinical characteristics such as age, number of comorbidities, receipt of chemotherapy or screening mammogram, and type of radiation facility. We compared one-year overall, wound and skin, and deep tissue and bone complications between brachytherapy and WBI using specific procedure and diagnosis codes identified in Medicare claims. Results: Of the 29,648 women in our sample, 4,671 (15.8%) received brachytherapy. The median percent of patients receiving brachytherapy varied substantially across hospital referral regions (interquartile range: 7.5%-23.3%). In the bivariate analysis, 34.3% of women treated with brachytherapy had a complication compared to 27.3% of those who received WBI (P<0.001). After adjusting for patient and clinical characteristics, 35.3% (95% CI: 34.7, 35.8) of women treated with brachytherapy had a complication compared to 18.7% (95% CI: 18.2,19.2) treated with WBI (average predicted difference: 16.5%, 95% CI: 15.8, 17.3, P<0.001). While brachytherapy was associated with a 16.9% (95% CI: 10.0, 23.8, P<0.001) higher absolute percentage of wound and skin complications compared to WBI, there was no difference in deep tissue and bone complications. Conclusions: Brachytherapy is commonly used among Medicare beneficiaries; in some regions nearly one in four women who underwent adjuvant radiation received brachytherapy. After one year, wound and skin complications were significantly more common among women who received brachytherapy compared to those receiving WBI, but there was no difference in deep tissue and bone complications.
Frequency of TLE3 overexpression in breast carcinoma subtypes including a large cohort of triple-negative patients.
Authors: Basu Gargi D. , Ghazalpour Anatole , Arguello David , Ashfaq Raheela , Gatalica Zoran , McGinniss Matthew Jerome , Blevins Richard , Danenberg Kathleen D
Published: March 2020

1040

Background: The taxanes are an important class of agents for the treatment of a broad range of malignancies including breast cancer. They improve survival in patients with early stage and metastatic breast cancer. Transducin-like enhancer of split 3 (TLE3) is a transcriptional repressor which influences growth and microtubule stability and its expression has been implicated in response to taxane therapy in breast cancer. We investigated the tumor expression of TLE3 in breast cancer patients, including a large cohort of the triple negative subtype. Methods: We analyzed TLE3 (M-201), ER(1D5), PR(PgR636) and HER2/neu(Polyclonal) expression by immunohistochemistry in 978 breast cancer patients. Immunoreactivity was assessed by scoring the percentage of cells stained in each field and by the intensity of staining. Results: To sub-classify the 978 breast cancer patients, we utilized hormone receptors (ER and PR) and HER2 expression/amplification. Overall, 36% of the total breast cancer patients were hormone receptor positive, 15% were HER2 positive and 49% were triple negative. The percentage of triple negative patients was higher in our cohort, given the fact that molecular profiling services are used more frequently for this subtype. A total of 477 patients were triple negative of which 61% stained positive for TLE3 expression. Of the 150 HER2 positive patients, 73% stained positive for TLE3 expression as compared with 82% TLE3 positivity in the 351 hormone receptor positive patients. By pairwise comparison, the hormone receptor positive vs triple-negative subtype showed the highest statistical significance in ratios of TLE3 positives (p =2.5e-10). Conclusions: Our results show that TLE3 is over-expressed in the majority of HER2 positive and hormone receptor positive breast cancer patients. Interestingly, the frequency of over-expression of TLE3 was lowest in the triple negative subtype thereby making it more important to identify those patients in this group who are most likely to respond to taxanes prior to therapy. To our knowledge, this is the first study providing a comprehensive review of TLE expression in breast cancer subtypes.
Molecular characteristics and metastasis predictor genes of triple-negative breast cancer.
Authors: Kuo Wen-Hung , Chang Yao-Yin , Hou Ming-Feng , Chuang Eric Y , Chang King-Jen
Published: March 2020

1043

Background: Triple-negative breast cancer(TNBC) is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible. Methods: Clinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated with oligonucleotide microarrays. A prognostic 45-gene signature for triple-negative breast cancer was identified using Student’s t test and receiver operating characteristic analysis. Results: Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A novel 45-gene signature giving 98% predictive accuracy in distant metastasis recurrence was identified in our triple-negative patient cohort. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% CI 1.04-5.06, Cox P = 0.04), outperforming five other published breast cancer prognostic signatures. The prognostic signature was statistically predictive with the node-negative triple-negative patients in the validation cohort. Conclusions: The 45-gene prognostic signature identified in this study revealed that TGF-β signaling in immune/inflammatory regulation may be critically involved in distant metastatic invasion of TNBC. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of metastasis recurrence for early-stage triple-negative patients.
Racial differences in outcomes of triple-negative breast cancer.
Authors: Pacheco Jose , Gao Feng , Bumb Caroline , Ellis Matthew J. , Ma Cynthia X.
Published: March 2020

1048

Background: The incidence and mortality of breast cancer can differ significantly among racial and ethnic groups. African American (AA) women have a lower incidence of breast cancer, but higher mortality compared to other racial groups. Triple negative breast cancer (TNBC: negative for the expression of estrogen receptor, progesterone receptor and HER2), which is an aggressive type of breast cancer, occurs more frequently in AA women. The few studies addressing whether racial differences exist in the outcomes of patients with TNBC have yielded inconsistent results. Methods: The Washington University Medical Oncology Database captures the clinical information for all new patients (pts) seen at the Breast Oncology Clinic. Most of these pts reside in the St. Louis metropolitan area. Using this database, we performed a retrospective analysis to examine the association of race with the clinical presentation and outcome of TNBC in this geographically defined patient population. Results: Between May 2006 and March 2011, 506 pts with TNBC were entered in the database. Analysis was done on 499 patients for whom follow up data is available. The median follow up (F/U) time was 24.5 months and the median age at diagnosis was 53 (24 to 98) years. Thirty percent of pts were AA. Only 5% presented with stage IV at diagnosis and the majority of tumors (86%) were high grade. Neoadjuvant chemotherapy was administered in 151 pts, 22% of whom achieved a pathologic complete response (pCR). There was no significant difference between races in the age of diagnosis, F/U time, tumor stage, grade, frequency of receiving neo/adjuvant chemotherapy and pCR rate to neoadjuvant chemotherapy. There was no difference in disease free survival (DFS) and overall survival (OS) between AA and other racial groups by either univariate or multivariate analysis that took into account tumor stage, grade, patient age and menopausal status. The HR for OS was 1.154 (CI 0.772 – 1.725, p value 0.4860) and for DFS it was 0.947 (CI 0.650 – 1.380, p value 0.7764) in AA compared to other races. In the 92 pts who recurred, there was no racial difference in time from recurrence to death. Conclusions: Race does not significantly affect the clinical presentation or outcome of TNBC in the St. Louis metropolitan area.
A prognostic model for predicting breast cancer (BC)-related survival in operable triple-negative (TN) patients (pts).
Authors: Munzone Elisabetta , Botteri Edoardo , Bagnardi Vincenzo , Sciandivasci Angela , Aurilio Gaetano , Adamoli Laura , Esposito Angela , Rotmensz Nicole , Goldhirsch Aron , Nole Franco
Published: March 2020

1049

Background: TNBC represent a heterogeneous disease in terms of biology, prognosis, and treatment response. We propose a prognostic model to identify homogeneous subgroups of patients and tailor risk-adapted adjuvant therapies indications. Methods: We analyzed 1,049 pts operated in our institute from 1997 to 2007 for early TNBC. Pts who received neoadjuvant chemotherapy (CT), with T4 tumors or previous history of cancer were excluded. Death from BC was the primary endpoint of the study. We calculated an individual predicted risk using a multivariable Cox regression model, with age, tumor size, number of positive lymph nodes and Ki-67 analyzed as continuous covariates, and tumor grade and perivascular invasion as categorical covariates. Results: Median age was 52 years, 562 (53.4%) and 670 (65.1%) pts had a pT1 and pN0 TNBC, respectively. Median Ki-67 was 48%. Adjuvant CT regimens were distributed as follows: classical CMF 388 (37.0%), anthracycline containing regimens 455 (43.4%), taxanes 12 (1.1%), other regimens 66 (6.3%) and no CT 128 (12.2%). After a median follow-up of 6 years, 131 deaths from BC were observed (5-year cumulative incidence 11.9%). At multivariable analysis, age, tumor size, number of positive lymph nodes, Ki-67, tumor grade and perivascular invasion were associated with the risk of death and were included in the prognostic model. Its predictive accuracy was good (C-index 0.73). We subsequently identified three homogeneous prognostic subgroups - low, medium and high-risk - according to the tertiles values of the predicted risk. The outcomes are shown in the table. Conclusions: We could identify homogeneous prognostic subgroups of TNBC pts according to clinical-pathological features. This prognostic model suggests that the use of CT in TN low-risk pts might be questionable. We are currently externally validating this model on a different series of pts. [Table: see text]
A heuristic platform for clinical interpretation of cancer genome sequencing data.
Authors: Van Allen Eliezer Mendel , Wagle Nikhil , Kryukov Gregory , Ramos Alexis , Getz Gad , Garraway Levi A.
Published: March 2020

10502

Background: The ability to identify and effectively sort the full spectrum of biologically and therapeutically relevant genetic alterations identified by massively parallel sequencing may improve cancer care. A major challenge involves rapid and rational categorization of data-intensive output, including somatic mutations, insertions/deletions, copy number alterations, and rearrangements into ranked categories for clinician review. Methods: A database of clinically actionable alterations was created, consisting of over 100 annotated genes known to undergo somatic genomic alterations in cancer that may impact clinical decision-making. A heuristic algorithm was developed, which selectively identifies somatic alterations based on the clinically actionable alterations database. Remaining variants are sorted based on additional heuristics, including high priority alterations based on presence in the Cancer Gene Census, biologically significant cancer genes based on presence in COSMIC or MSigDB, and low priority alterations in the same gene family as biologically significant cancer genes. The heuristic algorithm was applied to whole exome sequencing data of clinical samples and whole genome sequencing data from a cohort of prostate cancer samples processed using established Broad Institute pipelines. Results: Application of the heuristic algorithm to the prostate cancer whole genome rearrangement data identified 172 (out of 5978) rearrangements involving actionable genes (averaging 2-3 events per tumor). Furthermore, two clinical samples processed prospectively were analyzed, yielding three potentially actionable alterations for clinical review. Conclusions: The heuristic model for clinical interpretation of next generation sequencing data may facilitate rapid analysis of tumor genomic information for clinician review by identifying and prioritizing alterations that can directly impact care. Our platform can also be applied to research data to prospectively explore clinically relevant findings from existing cohorts. Future analytical approaches using heuristic or probabilistic algorithms should underpin a robust prospective assessment of clinical cancer genome data.
Rare epidermal growth factor receptor (EGFR) mutations in 10,117 patients with non-small cell lung cancer (NSCLC) evaluated by the French ERMETIC IFCT network: Clinical, molecular, and survival data.
Authors: Beau-Faller Michele , Prim Nathalie , Ruppert Anne-Marie , Nanni Isabelle , Besse Benjamin , Escande Fabienne , Lizard Sarab , Pretet Jean-Luc , DE Cremoux Patricia , DE Fraipont Florence , Rouquette Isabelle , Solassol Jerome , Bieche Yvan , Cayre Anne , Voegeli Anne-Claire , Quoix Elisabeth , Morin Franck , Blons Helene , Cadranel Jacques
Published: March 2020

10507

Background: The EGFR exon 19 deletion and exon 21 L858R mutation are associated with response to EGFR-TKI. However, the correlation with response to EGFR-TKI remains unclear for rare exon 18 and 20 EGFR mutations. We investigated the clinical features of NSCLC patients with exon 18 and exon 20 EGFR mutations, analyzed response to EGFR-TKI and patient's survival. Methods: Between 2005 and 2011, all rare exon 18 and 20 EGFR mutations were collected from 10117 cases of NSCLC in 15 of 28 French NCI molecular genetic laboratories. Results: During the study period, EGFR mutations were identified in 1048 (10.35%) out of the 10117 performed tests and 108 rare mutations (10.3%) were identified in 103 patients, including 25 never identified mutations. Among them, 48 mutations were localized at exon 18 and 60 at exon 20, with 3 out of the 4 identified T790M exon 20 mutations associated with L858R mutation. Only 5 other rare mutations were associated with EGFR 19 or 21 mutations. 38 patients received EGFR-TKI (erlotinib, n=32; gefitinib, n=6). Among the 36 evaluable patients, best response on TKI was progression in 18 patients (50%), stabilization in 11 (30.5%) and partial response in 7 (19.4%). Tumor control rate observed in exon 18 mutations was 61% (8/13) and 50% (13/26) in exon 20 mutations. For the EGFR-TKI treated patients, the median PFS was 6 months (2-53). Median OS was 15 months (1-92), with no difference between the EGFR-TKI treated patients or not. Conclusions: Prevalence of rare EGFR mutations was 1.06% of all tested NSCLC and 10.35% of all EGFR mutations. Tumor control on TKI was observed in half of the patients. Reports of NSCLC harboring rare mutations are important to help the decision-making process in this subset of patients.
Effect of therapeutic targeting of the oncogene EMP2 in triple-negative breast cancer on tumor load.
Authors: Wadehra Madhuri , Kiyohara Meagan , Fu Maoyong , Gordon Lynn K , Braun Jonathan
Published: March 2020

1052

Background: Understanding tumor induced angiogenesis is a challenging problem with important consequences for the diagnosis and treatment of cancer. In this study we define a novel function for the tetraspan epithelial membrane protein-2 (EMP2) in the control of neoangiogenesis. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple negative breast, ovarian, and endometrial tumors. In breast cancer, EMP2 is highly expressed on the majority of invasive tumors examined, and in particular 70% of triple negative breast tumors showed surface expression of this marker. In this study, we examine the control of EMP2 on the tumor microenvironment and further characterize its therapeutic efficacy in breast cancer. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels altered the tumor microenvironment. Cells were tested for their expression of pro-angiogenic proteins HIF-1a and VEGF-A as well as for their ability to induce endothelial cell migration and capillary like tube formation. Cells with modulated EMP2 levels were also tested in vivo for tumor formation and examined for histological changes in the tumor microenvironment. In addition, we recently constructed a fully human EMP2 IgG1 and determined its therapeutic efficacy in a number of triple negative breast cancer cells. Results: In vitro, upregulation of EMP2 promoted VEGF expression through a HIF-1a dependent pathway and resulted in successful capillary-like tube formation. In contrast, reduction of EMP2 correlated with reduced HIF-1a and VEGF expression with the net consequence of poorly vascularized tumors in vivo. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load with a significant improvement in survival. Conclusions: Clinically, EMP2 has been shown to correlate with poor survival, and these results suggest that this occurs in part through its control on tumor vasculature. In addition, we provide additional evidence on the potent cytotoxic effects of EMP2 treatment in vivo.
Prognostic significance of LINE-1 methylation level in the upper gastrointestinal cancer.
Authors: Baba Yoshifumi , Watanabe Masayuki , Iwagami Shiro , Shigaki Hironobu , Ishimoto Takatsugu , Iwatsuki Masaaki , Baba Hideo
Published: March 2020

10523

Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in long interspersed nucleotide element-1 (LINE-1) is a good indicator of global DNA methylation level. Although LINE-1 methylation level is attracting interest as a useful marker for predicting cancer prognosis, the prognostic significance of LINE-1 hypomethylaiton in the upper gastrointestinal cancer [i.e., esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC)] remains unclear. Methods: Using 217 ESCC and 207 GC specimens, we quantified the LINE-1 methylation using bisulfite-pyrosequencing technology. During the follow-up, there were a total of 63 ESCC recurrences, 51 ESCC deaths and 56 GC deaths. The median follow-up time for censored patients was 2.8 years. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical, epidemiological, and pathological variables. The term “prognostic marker” is used throughout this study according to the REMARK Guidelines. Results: ESCCs and GCs showed significantly lower LINE-1 methylation levels compared to matched normal mucosa (p<0.0001). In ESCC, LINE-1 hypomethylation was significantly associated with disease-free survival [log-rank p=0.0008; univariate HR= 2.32, 95% confidence interval (CI) 1.38-3.84, p=0.0017; multivariate HR=1.81, 95% CI 1.06-3.05, p=0.031] and cancer-specific survival (log-rank p=0.0020; univariate HR=2.21, 95% CI 1.33-3.60, p=0.0026; multivariate HR=1.87, 95% CI 1.12-3.08, p=0.018]. We found a significant modifying effect of the tumor stage on the relationship between LINE-1 methylation and the recurrence rate (P for interaction = 0.031). In GC, LINE-1 hypomethylation was significantly associated with cancer-specific survival (log-rank p=0.029; univariate HR=2.01, 95% CI 1.09-3.99). Conclusions: LINE-1 hypomethylation is associated with shorter survival in both ESCC and GC, suggesting that it has potential for use as a prognostic biomarker.
VEGF polymorphism may be associated with overall survival in lapatinib-treated breast cancer patients with brain metastases.
Authors: Spraggs Colin F. , Li Li , Briley Linda P. , Joshi Alaknanda , Florance Allison M. , King Karen , Parham Laura R
Published: March 2020

10532

Background: Lapatinib is a dual HER2/EGFR tyrosine kinase inhibitor (TKI) approved in combination with capecitabine or letrozole for patients with HER2+ metastatic breast cancer (MBC). Consistent with TKI therapies, patient response is variable and suggestive of additional determinants of sensitivity and resistance. This exploratory pharmacogenetic study sought to identify germline genetic variants that associate with lapatinib treatment outcomes in HER2+ MBC patients. Methods: Fifty five functional single nucleotide polymorphisms (SNPs) in 24 candidate genes were evaluated in a subset of MBC patients participating in two clinical trials: EGF105084: lapatinib monotherapy in HER2+ MBC patients with recurrent brain metastases following trastuzumab and cranial radiotherapy (n=120) and EGF104900: lapatinib plus trastuzumab (n=92) and lapatinib monotherapy (n=103) in HER2+ MBC patients with disease progression following trastuzumab. Testing for associations of SNPs with progression free survival (PFS) and overall survival (OS) during lapatinib treatment was performed using Cox proportional hazards methods, with covariate adjustment. Markers were considered to be significantly associated if they achieved a predefined multiple testing threshold of p<0.0003. Results: No SNPs were significantly associated with PFS in either study. A SNP in VEGFA (rs3025039, 936C>T) was significantly associated with improved OS (p=0.0002) for the T allele carriers, with an allelic hazard ratio of 0.21 (0.08-0.52) in EGF105084. The association was not seen in EGF104900. This SNP is located in the 3’ UTR gene region, the T allele is associated with lower serum VEGFA levels and reduced breast cancer risk [Krippl et al, 2003, Int J Cancer 106: 468; Kataoka et al, 2006, Cancer Epidemiol Biomarkers Prev, 15:1148]. Conclusions: A germline variant in VEGFA may be associated with survival outcome in MBC patients with brain metastases who are treated with lapatinib. This may represent activation of VEGF angiogenic pathways to overcome HER2 inhibition in patients carrying the higher expression genotype. These associations are considered exploratory and require confirmation in an independent dataset.
Prognostic and diagnostic value of Ewing family of tumors (EFTs)-associated fusion transcripts detected in peripheral blood specimens.
Authors: Przybyl Joanna , Kosela Hanna , Wiater Katarzyna , Ptaszynski Konrad , Szumera-Cieckiewicz Anna , Falkowski Slawomir , Lugowska Iwona A. , Debiec-Rychter Maria , Siedlecki Janusz A , Rutkowski Piotr
Published: March 2020

10538

Background: EFTs are characterized by chromosomal translocations leading to formation of oncogenic EWSR1-FLI1 fusion gene in 85-90% of cases. The aim of the study was to detect circulating tumor cells (CTCs) carrying EWSR1-FLI1 fusion transcript in peripheral blood and assess their added value to standard diagnostic procedures and utility as a prognostic marker in EFTs. Methods: 10mL of whole blood was collected from 35 untreated adult EFTs patients at the diagnosis (period: 2008-2011, median age 27 years) and 13 healthy controls. 13 patients presented metastatic disease (M1) at the diagnosis. Nested RT-PCR was applied in triplicate for the detection of EWSR1-FLI1 transcript. Blood specimen was regarded CTC-positive when at least 2 out of 3 nested RT-PCR assays were positive and results were confirmed by sequencing. FISH assay for EWSR1 rearrangement was performed on FFPE tumor tissue in 28 available cases. Median follow-up was 16 months. Results: EWSR1-FLI1 transcript was detected in peripheral blood of 71.4% (n=25) of patients. FISH assay was positive for EWRS1 rearrangement in 58% of cases. In 10 patients, where FISH assay could not be performed due to insufficient quality or lack of material, nested RT-PCR provided confirmation of immunopathological diagnosis. Specificity of RT-PCR blood test in healthy control was 91.4% (12/13 negative; p=0.0001). Median overall survival (OS) was 18 months. CTC-positive patients showed the trend for longer OS than CTC-negative patients (1-year OS: 89% vs. 58%; p=0.07), but longer follow-up is needed. Conclusions: Our results show that the fusion transcript detection in peripheral blood specimens may be a useful additional test to the standard clinicopathological diagnosis of EFTs. High detection rate of EWSR1-FLI1 transcript in peripheral blood of EFTs patients at the diagnosis may imply EFTs as a systemic disease with clinically evident metastases or micrometastases at presentation. Prognostic significance of CTCs in EFTs warrants further studies.
Detection and HER2 expression of circulating tumor cells in advanced gastric cancer patients.
Authors: Matsusaka Satoshi , Chin Keisho , Ogura Mariko , Suenaga Mitsukuni , Shinozaki Eiji , Mizunuma Nobuyuki , Sano Takeshi , Yamaguchi Toshiharu , Yamamoto Noriko , Ishikawa Yuichi , Mishima Yuji , Terui Yasuhito , Hatake Kiyohiko
Published: March 2020

10541

Background: This study was aimed at detecting and HER2-expressiong circulating tumor cells (CTC) in peripheral blood of chemo-naïve or chemo-resistant patients with advanced gastric cancer. Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital in the Japanese Foundation for Cancer Research and provided informed consent. The study population consisted of patients of age 18 years or older with histologically proven advanced gastric cancer. A total of 140 patients with advanced gastric cancer were enrolled into a prospective study. We used CellSearch system for detection and HER2 expression for CTC. Results: We detected ≥1 CTC/7.5ml in 80 of 140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 CTC-positive patients (23.8%), including 6 patients with HSR2-negative primary tumors. 21 patients with HER2-positive primary tumors administered trastuzumab in combination with chemotherapy (Xeloda+cisplatin; 15, weekly Paclitaxel; 5). We detected ≥1 CTC/7.5ml at the baseline in 11 of 20 patients with trastuzumab treatment. HER2-positive CTCs were observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2-positive CTC at the baseline were shorter PFS than those with HER2-negative CTC at the baseline. Conclusions: HER2 expression on CTC was associated with chemo-resistance. Information on the HER2 status of CTC might be helpful for stratification of HER2-directed therapies.
Serum hepatocyte growth factor and interleukin-6 as prognostic markers for stage III non-small cell lung cancer.
Authors: Ujiie Hideki , Tomida Mikio , Akiyama Hirohiko , Okada Daisuke , Nakajima Yuki , Sakai Hiroshi , Takiguchi Yuichi , Tanzawa Hideki
Published: March 2020

10542

Background: We surveyed prognostic biomarkers for resectable non-small cell lung cancer (NSCLC). Methods: We obtained preoperative serum from 109 patients admitted to our facility, and measured the levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), and nicotinamide N–methytransferase (NNMT) in the sera by the ELISA method. We also examined the clinical backgrounds of the patients. Results: The median HGF and IL-6 contents in sera from 109 patients were 860 pg/ml and 2.7 pg/ml, respectively. Analysis of survival curves indicated that HGF or IL-6 levels higher than the median were associated with poor overall survival (HGF, P = 0.019; IL-6, P = 0.002). On the other hand, carcinoembryonic antigen (CEA), a known tumor marker, and NNMT, which we found to be a candidate tumor marker, exhibited no correlation with the prognosis. The tumor status (pT factor) and stage were strong prognostic indicators (P < 0.001). In addition, we analyzed stage III lung cancer alone. Higher HGF or IL-6 levels were associated with poor overall survival (HGF, P = 0.016; IL-6, P = 0.013). Disease-free survival was also affected by these cytokine contents, but not statistically significantly. The prognosis of patients with adenocarcinomas (ADC) was better than that of patients with other histological types. However, the pT factor and nodal status (pN factor) were not associated with the survival of stage III patients. Conclusions: The levels of HGF and IL-6 in serum could be useful prognostic indicator of the survival of stage III NSCLC patients undergoing surgery and chemotherapy.
Preclinical evaluation of selective inhibitors of nuclear export (SINE) in basal-like breast cancer (BLBC).
Authors: McCauley Dilara , Landesman Yosef , Senapedis William , Kashyap Trinayan , Saint-Martin Jean-Richard , Plamondon Louis , Sandanayaka Vincent , Shechter Sharon , Froim Doriana , Nir Raphael , Williams Jennifer , Chin Lynda , Benes Cyril , Mirza Mansoor Raza , Kauffman Michael , Shacham Sharon
Published: March 2020

1055

Background: Basal-like breast cancers (BLBC) compose up to 15% of breast cancer (BC) and are usually triple negative characterized by lack of ER, PR, and HER-2 amplification. In addition, most BRCA1-associated BCs are BLBC and TNBC, expressing basal cytokeratins and EGFR. BLBC is characterized by an aggressive phenotype, high histological grade, and poor clinical outcomes: high recurrence and metastasis rates. CRM1 (XPO1) is the exclusive nuclear exporter of multiple Tumor Suppressor Proteins (TSP) including p53, p21, BRCA1&2, pRB, FOXO. CRM1 inhibition forces nuclear accumulation of TSPs, inducing apoptosis in cancer cells. KPT-SINE are novel, small molecule, irreversible inhibitors of CRM1 with potent anti cancer activity. Methods: The Cancer Genome Atlas (TCGA) and BC cell line databases were used for mRNA analyses. MTT assay was used to determine the cytotoxic effect of KPT-SINE (KPT-185 and KPT-330) on 44 breast cell lines including luminal A, luminal B, HER2 positive, BLBC and TNBC cells. The effect of KPT-330 treatment on tumor growth was tested in vivo in the TNBC model MDA-MB-468 xenograft. Results: Analyses of nuclear pore complex (NPC)-related mRNA levels (including CRM1) showed clear separation of BCs into high and low NPC expression. BLBC subtype was enriched with high NPC transcripts while luminal BC was enriched in low NPC levels (p<1.53e-20). High NPC levels had higher mutation levels in BRCA2 (cor=0.33, p=1.83e-8) and ABL1. NPC expression was inversely correlated with ER mRNA expression (cor=-0.58, p=1.37e-7). KPT-SINE showed potent cytotoxicity on >75% of the cell lines (IC50 values <1 μM). Only three of 24 TNBC cell lines displayed IC50 values >1.5 μM upon KPT-SINE treatment. Genomic analyses on all BC lines indicated that p53, PI3K/AKT and BRCA1 or 2 status did not affect cytotoxicity. In MDA-MB-468 xenograft, KPT-330 displayed efficacy in a dose-dependent manner inhibiting nearly 100% of tumor growth compared with vehicle treated animals, and was well tolerated. Conclusions: These data show that NPC/CRM1 mRNAs are overexpressed in BLBC/TNBC and that CRM-1 mediated nuclear export inhibition by SINE represents a potentially novel and well tolerated therapy for BLBC / TNBC.
Hybrid PET-MRI of the breast: A promising tool for the characterization of breast tumors.
Authors: Pinker-Domenig Katja , Bickel Hubert , Bogner Wolfgang , Magometschnigg Heinrich , Gruber Stephan , Dubsky Peter Christian , Pluschnig Ursula , Rudas Margaretha , Bago-Horvath Zsuzsanna , Helbich Thomas
Published: March 2020

10570

Background: To evaluate if PET-MRI of breast tumors improves staging of breast cancer and obviates unnecessary breast biopsies. Methods: 106 patients with breast tumors detected by mammography or ultrasound and classified as BIRADS 3-5 were included in this IRB approved prospective study. All patients were examined with dedicated 18FDG-PET-CT and 3T multiparametric MRI of the breast. Examinations were scheduled no longer than 7 days apart. MRI protocol included: a diffusion-weighted sequence (DWI), a T2-w sequence and a contrast-enhanced combined high temporal and spatial resolution 3D-T1-w sequence before and after application of a standard dose Gd-DOTA. For PET-CT patients fasted at least 6 h before injection of approx. 300 MBq 18F-FDG based on the patients weight. Scanning was started 45 min after injection. Blood glucose levels were <150 mg/dl. A prone PET dataset over the breasts was acquired using a positioning device allowing the same patient geometry as the breast MRI coil. CT data was used for attenuation correction. Co-registration of imaging data and image fusion were performed. PET-MRI was assessed for lesion morphology and EH-kinetics according to BI-RADS and restricted diffusivity with an ADC threshold 1.25 x10-3mm2/s set as the cut-off for malignancy. Lesions were assed for 18F-FDG–avidity and classified as positive when 18F-FDG-uptake was greater than blood-pool activity. Additionally, nodal status was recorded for each technique and patient. Histopathology was used as the standard of reference. Results: PET-MRI achieved an excellent sensitivity of 100%. Specificity was increased from 68% to 80% as compared to routinely used MRI. Diagnostic accuracy of PET-MRI for diagnosis of breast cancer was 95%. PET-MRI would have obviated unnecessary breast biopsies in 80% of benign breast lesions without missing any cancers. Additionally, PET-MRI increased sensitivity in the detection of lymphnode metastases from 70% to 87% compared to MRI alone. Conclusions: With PET-MRI unnecessary breast biopsies can be obviated without missing any cancers. PET-MRI increases overall diagnostic accuracy in the diagnosis of breast cancer and lymphnode metastases for an accurate staging.
Antagonistic activity of acolbifene, fulvestrant, tamoxifen, and raloxifene on cancer-associated genes in the mouse mammary gland.
Authors: Calvo Ezequiel , Luu-The Van , Martel Céline , Labrie Fernand
Published: March 2020

10583

Background: The efficacy and exceptionally good tolerance of estrogen blockade in the treatment of breast cancer is well recognized. Acolbifene (ACOL) is a novel and unique SERM completely free of estrogen-like activity in both the mammary gland and uterus. To better understand the specificity of ACOL, we have investigated its effect on the expression of a set of genes modulated by estradiol (E2) in the mouse mammary gland. Methods: ACOL, tamoxifen (TAM), raloxifene (RALOX) and fulvestrant (FULV) were administered (0.01 mg/mouse; sc) to ovariectomized (OVX) mice or to OVX mice simultaneously treated with E2 (0.05 µg/mouse; single sc injection). Microarray screening followed by Q_RTPCR was used to identify a reproducible set of E2 responsive genes. Results: From 128 genes significantly modulated by E2, 108 genes were up-regulated and 20 were down-regulated. Forty-nine of these genes were associated with tumorigenesis while 22 are known to be associated with breast cancer. This set of 49 genes were used to determine the specificity of ACOL compared to another pure antiestrogen in the mammary gland and uterus, namely FULV, as well as to the mixed estrogen antagonists/agonists TAM and RALOX, in their ability to block the effect of E2. Efficacy of reversal of the effect of E2 was 94%, 63%, 45% and 90% for ACOL, FULV, TAM and RALOX, respectively. The overlap between all treatments was 30.6% (15/49). ACOL reversed the effect of E2 on 42 of the 49 (85.7%) cancer-related genes. Between the genes up-regulated by E2 and reversed by ACOL, seven are considered as prognostic markers in breast cancer, namely Fgfr3, Fos12, Junb, Jdp2, Gdf15, Greb1 and Tgm2. On the other hand, two genes down‑regulated by E2, namely Foxa1 and Fgfr2, were restored by ACOL. Conclusions: Taken together, these data offer new information for a better understanding of the previously demonstrated potent tumoricidal action of ACOL in human breast cancer xenografts. The data also suggest, under the tested conditions, superiority of ACOL over TAM and the other compounds to reverse the effect of E2 on specific gene expression, thus supporting the interest of this new 3rd generation SERM for the hormonal therapy and prevention of breast cancer.