bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene expression of the MAPK pathway in osteosarcoma.
Authors: Lopes Luana Joyce Silva , Petrilli Antonio Sergio , Tesser-Gamba Francine , Alves Maria Teresa Seixas , Garcia-Filho Reynaldo Jesus , Toledo Silvia R. C.
Published: March 2020

10534

Background: Osteosarcoma (OS) is the most common malignant bone tumor in adolescents. A feature of the OS is its high risk of lung metastasis. Unlike other sarcomas, OS does not have genetic markers. We suggest that abnormalities in the expression levels of genes involved in important cell signaling pathways, as MAPKs pathway, may contribute to OS progression and aggressiveness. In a recent study, we found an overexpression of MAPK7 gene in prechemotherapy specimens when compared to postchemotherapy specimens and when compared with normal bone. This previous study suggests that MAPK7 overexpression may be contributing to the worse response to treatment and therefore a poor overall survival. To understand the relationship between the OS genesis process and the MAPK pathway, we investigated the expression of genes involved in the regulation of MAPK pathway (MAP2K5, MAP2K6, MAP3K1, MAP3K3, MAP4K3 and DUSP1). Methods: Total RNA was extracted from 68 tumor samples obtained from 28 patients (28 prechemotherapy specimens, 28 postchemotherapy specimens and 12 metastasis specimens) and five normal bone tissues. cDNA was synthesized and expression of the six genes were determined by quantitative real-time PCR. Clinical variables were correlated with gene expression. Results: MAP2K6 and MAP4K3 had a similar gene expression profile. Both genes were overexpressed in postchemotherapy specimens and were strongly associated with important clinical parameters as presence of metastasis (P=0.0159 and P=0.0014, respectively), shorter overall survival (P=0.0040 and P=0.0040, respectively) and disease progression (P=0.0142 and P=0.0109, respectively). DUSP1 overexpression in postchemotherapy specimens was related with metastasis at diagnosis (P=0.0004), worse response to treatment (P=0.0009) and disease recurrence (P=0.0039). MAP2K5, MAP3K1 e MAP3K3 showed no significant correlations in the present study. Conclusions: The overexpression of MAP2K6, MAP4K3 and DUSP1 in postchemotherapy specimens presented a significant association with poor prognosis. The current study suggests that these genes could play an important role in OS tumorigenesis and may be in the future new therapeutic targets in OS treatment.
Relationship of the topography of KIT exon 11 alterations and predictive value for PFS in patients with advanced GIST: Results of the BFR14 prospective French Sarcoma Group randomized phase III trial.
Authors: Emile Jean-François , Ray-Coquard Isabelle , Bui Binh , Adenis Antoine , Bertucci François , Duffaud Florence , Cupissol Didier , Chevreau Christine , Bompas Emmanuelle , Coindre Jean-Michel , Mir Olivier , Pérol David , Chabaud Sylvie , Blay Jean-Yves , Le Cesne Axel
Published: March 2020

10542

Background: The mutations of KIT exon 11 are those most frequently observed in GIST, but there is a substantial level of heterogeneity in their nature and topography. We investigated the impact of the type of KIT exon 11 mutations on clinical presentation and outcome under imatinib in advanced GIST patients (pts) included in the BFR14 study. Methods: Among the 434 pts included, 167 were identified as having GIST with KIT exon 11 mutation (85% of all KIT mutations and 73% of all mutations available in the entire cohort). We analyzed the topography of the mutations and identified 3 groups (G) of mutations according to the first codon involved in the genetic alteration in which the precise topography was available (from codon 549 to 579). The distribution of these G in the different clinical presentations was investigated, as well as their predictive value for progression-free (PFS) and overall survival (OS). Results: Three G with distinct sites of altered codons were distinguished: G1 whose 1st mutated codon was <556 (n=41, 24.5%), G2 whose 1st mutated codon was 557 and 558 (n=74, 44.3%), including those with the deletion 557-558 (n=37, 22.1%), and G3 whose 1stmutated codon was 559 and beyond (n=52, 31.1%). All investigated parameters at inclusion, gender, tumor site and size, site of metastases, age, PS, CD34 expression, biological characteristics were well balanced between the three G of patients. Pts of G2 reached a statistically difference in terms of complete response under imatinib (p=0.028). In contrast, this G have the poorer PFS compared to the other two groups: the median PFS were 30.6 months (CI95%: 21.5;39.4), 49.4 months (CI95%: 33.5; 109.9) and 63.3 months (CI95%: 27.6; 84.7) for the G 2, 1 and 3 respectively (p=0.0176). OS was not significantly different in the 3 G of pts. Conclusions: Despite a favorable sensitivity to imatinib, GIST pts harbouring a genetic alteration initially involving the 557 and 558 codons develop statistically more secondary resistance than the others. These results deserve confirmation in other prospective series in advanced GIST and may be worth exploring in adjuvant series.
Imatinib plasma concentrations during long-term effective treatment of metastatic gastrointestinal stromal tumor.
Authors: Sawaki Akira , Inaba Kazuki , Hayashi Katsumi , Kanie Hiroshi , Owaki Toshihiro , Kimata Tsukasa , Suzuki Masato , Kawachi Aya , Orito Etsuro
Published: March 2020

10543

Background: Imatinib concentrations at one month after the start of imatinib have shown an association with clinical benefit in pts with gastrointestinal stromal tumors (GISTs) and a significant decrease of 30% within twelve months. This retrospective study investigated imatinib plasma concentrations in pts with metastatic GISTs in a long-term (≥2 years) effective treatment. Methods: 31 metastatic GIST pts, who had been treated with imatinib for two or more years in our hospital, were enrolled in this study. 11 pts were excluded because of adjuvant setting (n=5) and rejection to concentration testing (n=6). 20 pts were included in this study. GISTs were immunohistochemically diagnosed, and radiologically assessed as effective GIST by Choi’s criteria without relapse. Results: 10 pts were male, median age was 63 years (range, 31-84), and median imatinib exposure time was 3.5 year (range, 2-12). The median plasma concentration was 1093 ng/ml (range, 417-2091) and minimal level after at least five years was 789 ng/ml. imatinib concentration has no significant correlation with age, gender, gastrectomy, leukocyte count, platelet count, serum albumin, serum creatinine, cholesterol, and duration of imatinib exposure. Body surface area (BSA) isn’t directly associated with imatinib dose; median BSA of pts taking 300mg imatinib was 1.560 m2 and that of 400mg 1.595 m2, but minimal BSA of 400mg imatinib was 1.560 m2, which is higher than the minimum of 300mg. Conclusions: Plasma concentrations of long-term (≥2 years) response pts was scattered, but one of longer-term (≥5 years) response pts were more than 789 ng/ml. Effective imatinib plasma level might be more than 789 ng/ml and 400mg imatinib may be recommended for a pt with BSA(≥1.56 m2).
Fear of disease progression in patients with gastrointestinal stromal tumors (GIST).
Authors: Tielen Ronald , Custers Jose A.E. , Prins Judith , de Wilt Johannes HW , Gielissen Marieke F.M. , Van Der Graaf Winette T.A.
Published: March 2020

10549

Background: GIST are rare tumors and before 2000 patients had a dismal prognosis when metastasized. Since the introduction of imatinib and other tyrosine kinase inhibitors overall survival has increased from less than 1 year before 2001 to more than 5 years now. Research on psychosocial consequences for this particular cancer type is scarce. This study focuses on quality of life and fear of disease progression in GIST patients. Methods: Eighty patients with locally advanced or metastatic GIST, being treated with imatinib or sunitinib, from the Radboud University Nijmegen Medical Centre in the Netherlands were asked to participate. Patients completed self-report questionnaires including the EORTC-QLQ-C30, the Cancer Worry Scale, and the Fear of Cancer Recurrence Inventory. Results: Fifty two patients (median age 64.2; range 22-84 years) completed the questionnaires. Two subgroups were identified: patients with locally advanced (n= 27) and metastatic GIST (n= 25). Overall, GIST patients demonstrate a good global quality of life (EORTC-QLQ-C30 mean global health 76.1). However, 50% of them (n= 26) experienced high levels of fear of cancer progression (CWS cut-off point ≥ 14). High levels of fear were not associated with age, gender or between patients with locally advanced or metastatic GIST. Subgroup analyses revealed that patients with high levels of fear of disease progression showed significantly higher levels of psychological distress related to fear of cancer progression and more functional impairments including domains that can be disturbed by fear of cancer progression (e.g. work, daily and social activities, the ability to make future plans or set life goals). Conclusions: Despite a good overall quality of life, a substantial percentage of GIST patients experience high levels of fear of cancer progression, experiencing more psychological distress and more functional impairments compared to patients with low levels of fear. No relation was found with demographic variables nor with stage of disease. This research demonstrates that it is necessary to focus on more specific rather than general quality of life of GIST patients.
Results from a phase III trial (GRID) evaluating regorafenib (REG) in metastatic gastrointestinal stromal tumour (GIST): Subgroup analysis of outcomes based on pretreatment characteristics.
Authors: Joensuu Heikki , Casali Paolo Giovanni , Reichardt Peter , Kang Yoon-Koo , Blay Jean-Yves , Rutkowski Piotr , Gelderblom Hans , Hohenberger Peter , Leahy Michael Gordon , von Mehren Margaret , Badalamenti Giuseppe , Blackstein Martin E. , Le Cesne Axel , Schoffski Patrick , Maki Robert G. , Xu Jian-Ming , Nishida Toshirou , Kappeler Christian , Kuss Iris , Demetri George D.
Published: March 2020

10551

Background: REG, an oral receptor kinase inhibitor with activity against KIT, PDGFR, VEGFR, FGFRs, and other oncologic targets, demonstrated significant improvement in progression-free survival (PFS) over placebo (PL) in a phase III study (GRID) of patients (pts) with advanced GIST following failure of at least imatinib (IM) and sunitinib (SU). To understand the impact of pts’ baseline characteristics on outcome, we performed an exploratory analysis of REG effects across pt subgroups based on sex, age, and mitotic index of primary GIST tissue, as well as duration and number of lines of previous therapies. Methods: Adult pts with metastatic GIST (n=199) progressing after at least IM and SU were randomized 2:1 to receive oral REG 160 mg or PL once daily for the first 3 weeks of each 4-week cycle. Subgroup analysis of centrally assessed PFS was performed, based on sex, age (<65, ≥65 years), mitotic index of primary GIST (<5, ≥5 to <10, ≥10 mits/50 hpf), duration of IM and SU treatment (<6, ≥6 to <18, ≥18 months), and number of prior anticancer treatment lines (2 or ≥3). Mitotic index data on primaries were available for 119 patients. Results: REG demonstrated improvement in PFS vs PL in all subgroups, as summarized in the Table. Conclusions: REG had substantial efficacy in all patient subgroups included in this analysis. Clinical trial information: NCT01271712. [Table: see text]
A risk-based individualized follow-up after complete surgery as an effective procedure to reduce the relapse (R) impact in GIST patients (pts).
Authors: Palesandro Erica , Galizia Danilo , D'Ambrosio Lorenzo , Boccone Paola , Aliberti Sandra , Venesio Tiziana , Manca Antonio , Bertotto Ilaria , Chiara Gabriele , Russo Filippo , Campanella Delia , Pignochino Ymera , Aglietta Massimo , Grignani Giovanni
Published: March 2020

10552

Background: FU care poses a burden on both pts and health system. FU aims to precociously identify recurrences, metastases or treatment-related adverse events so to undertake the appropriate therapy as soon as possible. Guidelines (NCCN, ESMO) admit lack of knowledge on optimal surveillance, but suggest FU based on experts’ opinion and risk stratification. Moreover, tumor burden (TB) is a well known negative prognostic factor (Van Glabbeke 2005). Therefore, low-TB at R might affect final outcome. To identify the impact, if any, of regular FU, we examined our prospectively collected database looking for Rs in which the early detection affected both clinical management and, likely, the outcome. Methods: 140 pts were stratified (AFIP classification). High risk (HR) pts had complete history + physical examination (H&P) and CT every 3 mos for 2 years, 4 mos in 3rd year, 6 mos in the 4th and 5th yrs, yearly thereafter; intermediate (IR), low (LR) and very low risk (VLR) pts had H&P + CT every 4 mos for 2 years, every 6 mos up to the 5th year, then yearly. Rs were divided in: low-TB + completely resectable R (Group 1) and high-TB + disseminated R (Group 2). The number of CT needed to detect (NND) one R and the incidence of early (<6 mos) R was calculated. Overall survival (OS) was estimated by Kaplan-Meier method. Results: In 73 male and 67 female, median age 63 (23-82), risk stratification was: HR 73, IR 31, LR 28, VLR 8. After a median FU of 63 mos we observed 58 Rs: 25 (43%) and 33 (57%) in group 2 and 1, respectively. Relapsed pts genotype was KIT Ex11 72%; Ex9 10%; Ex13 3%; wild-type 15%. Median time to R was 16 mos (1-120). 21 pts underwent surgical resection of their R. 16 pts remained free from progression for a median of 90 mos. We detected 15 (26%) early Rs. NND was 17 and 32 CT for HR and non-HR pts, respectively. Group 1 and 2 median estimated OS was 112 and 87 mos (p=.05), respectively. Conclusions: Though retrospective, this series shows that FU may detect low-TB Rs. In principle, this might affect pts final outcome and, therefore, justify this costly effort. Since it is difficult to foresee a prospective randomized trial, a confirmation of these data in a different series might increase their reliability.
Significance of the vimentin expression in triple-negative breast cancer.
Authors: Yamashita Nami , Tokunaga Eriko , Kitao Hiroyuki , Tanaka Kimihiro , Taketani Kenji , Saeki Hiroshi , Aishima Shinichi , Oki Eiji , Morita Masaru , Maehara Yoshihiko
Published: March 2020

1056

Background: Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The treatment of patients with TNBC has been challenging due to the absence of these molecular targets and the heterogeneity of the disease. Therefore a better understanding of the molecular and histopathological features of TNBC and its heterogeniety is important for the development of a new therapeutic strategy and to improve the prognosis of TNBC. Recent studies suggest that there are links between TNBC and the epithelial-mesenchymal transition (EMT). To identify prognostic biomarkers and novel therapeutic targets, vimentin one of the most major factors associated with EMT was investigated in TNBC. Methods: Sporadic invasive ductal carcinoma specimens were obtained from 659 Japanese patients, and 90 (14%) cases were diagnosed as TNBC. The vimentin mRNA and protein expression levels were evaluated by quantitative RT-PCR and immunohistochemistry. Results: The mRNA expression of vimentin was significantly upregulated in the basal type breast cancer cell line. Immunohistochemically, the vimentin expression was significantly higher (p=0.0042) in TNBC compared to the other subtypes. Vimentin expression was associated with a younger age (p=0.016), high nuclear grade (p=0.023) and high Ki67 expression (p<0.0001), and a poorer prognosis in terms of both the recurrence-free survival (RFS) (p=0.0058) and overall survival (OS) (p=0.013) in TNBC patients. A multivariate analysis showed that vimentin expression was an independent prognostic factor for the RFS (p=0.043). Vimentin expression was also associated with a significantly shorter RFS (p=0.021) and OS (p=0.017) in patients with basal-like breast cancer (BLBC). Conclusions: The elevated expression of vimentin contributes to the aggressive phenotype and poor prognosis in TNBC. Vimentin expression might be useful as a biomarker for the prognosis of TNBC.
Relationship of FAP-alpha, ADAM12, WISP1, and SOX11 expression to tumor activity in aggressive fibromatosis: Demonstration of heterogeneity within and between cases.
Authors: Misemer Benjamin , Skubitz Amy , Manivel Carlos , Schmechel Stephen , Cheng Edward , Henriksen Jonathan , Koopmeiners Joseph , Skubitz Keith M.
Published: March 2020

10560

Background: Aggressive fibromatosis (AF) represents a group of tumors with an unpredictable clinical course and is characterized by a monoclonal proliferation of myofibroblasts. The optimal treatment for AF is unclear. In earlier gene expression studies we identified four genes, ADAM12, WISP1, SOX11, and FAP-alpha, that were uniquely overexpressed in AF compared with 16 different normal tissues. This study was designed to examine the expression of these four proteins in AF. Methods: Immunohistochemistry (IHC) was performed in 29 cases of AF, and analyzed by a pathologist with expertise in the field. Automated imaging analysis was performed to independently quantify IHC staining, nuclear size, and nuclear chromatin density. Nuclear size was determined on control slides. Slides were scanned using ScanScope XT (Aperio) and images were divided into tiled regions of interest (ROIs) for measurements. A nuclear chromatin density ratio (CDR), defined as the measure of nuclear area with light staining divided by nuclear area with dark staining, was quantified as a surrogate for nuclear activity. To compare the image analysis with pathologic examination, an operational definition of “morphologic tumor activity” (MTA) was determined by a pathologist using a scale of 1 (inactive), 2 (probably inactive), 3 (probably active), and 4 (active) on a random set of 322 ROIs. The MTA score was then correlated with the CDR. We also assessed the relationship of CDR to IHC staining intensity for each of the four proteins in ~26,000 ROIs derived from all 29 AF samples. Results: Different areas of AF cases had different degrees of MTA. The expression of the four proteins generally correlated with the areas of tumor that were pathologically more “active.” Staining was more intense in areas with larger more open nuclei suggesting “more active” regions. There was a significant correlation between MTA and log [CDR] (0.46, p<0.001). Conclusions: The results confirm, on the protein expression level, our earlier gene expression results, and demonstrate the regional variation of tumor activity within and among AF cases.
Prediction of metastatic behavior in high-grade pleomorphic soft tissue sarcomas by gene expression.
Authors: Skubitz Keith M. , Skubitz Amy , Xu Wayne , Luo Xianghua , Lagarde Pauline , Coindre Jean-Michel , Chibon Fred
Published: March 2020

10561

Background: The biologic heterogeneity of soft tissue sarcomas (STS) complicates treatment. Metastatic propensity may be determined by gene expression patterns that do not correlate well with morphology. In earlier studies, gene expression patterns were identified that distinguish 2 subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF). We reported the use of a gene set derived from these three studies to separate 73 high grade STS into groups with different probabilities of developing metastatic disease (PrMet). We wished to confirm our findings using an independent data set. Methods: We utilized these gene sets, hierarchical clustering (HC), Kaplan-Meier, and log-rank analyses to examine the Affymetrix HU_133 expression profiles of 309 STS. Results: HC using a pooled gene set derived from the AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Kaplan-Meier analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p=0.048), and also among the 4 different clusters defined by the second branch points (p<0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UDS) (p=0.0004). HC of the LipoD and UDS samples with the pooled probe set divided the samples into 2 groups with different PrMet (p=0.013, and 0.0002, respectively). HC of the UDS samples also showed 4 groups with different PrMet (p=0.0007). In contrast, HC found no subgroups of the LMS samples. Each individual gene set (AF-, RCC-, and OVCA-) separated the UDS samples into subsets of different metastatic outcome, but only the AF- gene set separated the LipoD samples, and no gene set identified LMS subsets. Conclusions: These data confirm our earlier studies and suggest that this approach may allow the identification of more than 2 subsets of high grade STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management.
Adjuvant radiotherapy (adj RT) for extremity and trunk wall atypical lipomatous tumor/well-differentiated LPS (ALT/WD-LPS): A French Sarcoma Group (GSF-GETO) study.
Authors: Cassier Philippe Alexandre , Kantor Guy , Bonvalot Sylvie , Lavergne Emilie , Stoeckle Eberhard , Le Pechoux Cécile , Meeus Pierre , Sunyach Marie-Pierre , Coindre Jean-Michel , Dubergé Thomas , Labib Alain , Lagrange Jean-Leon , Linassier Claude , Delcambre Corinne , Bay Jacques-Olivier , Leyvraz Serge , Penel Nicolas , Chabaud Sylvie , Duret Aude , Blay Jean-Yves
Published: March 2020

10582

Background: The role of adj RT in the management of ALT/WD-LPS remains controversial. Methods: 284 patients (pts) with operable ALT/WD-LPS, no history of previous cancer, CT or RT, treated between 1984 and 2011 and registered in the Conticabase database were included and described. Overall (OS) and local relapse free (LRF) survival were evaluated from the time of first treatment (trt). Their distributions were estimated by Kaplan-Meier method and compared between RT groups using Log-Rank test. Independent prognostic factors and adj RT, were explored with Cox model. Results: Among the 20 centers, 3 enrolled 58% of the pts. Median age at diagnosis was 61 (range 25-94), 146 pts (51%) were males, 223 (79%) pts had distal tumors while 35 (12%) and 26 (9%) had tumors involving the girdle and the trunk wall. The median size of primary tumors was 17 cm (range 2-48), 272 (96%) lesions were deep seated, 24 (9%) were multifocal within the same anatomical area. Surgery quality was unknown for 42 pts. Among the remaining pts, 102 (43%) were R0, 130 (54%) R1 and 8 (3%) R2. Adj RT was given to 129 pts (45%). Pts who received adj RT had larger tumors (p=0.034), involving more often the distal limbs (p<0.001) and were more often multifocal in the same anatomical area (p=0.009). The use of adj RT varied across centers and along the study period. Other characteristics, including margin resection, were balanced between RT groups. Median follow-up for the whole population was 38.6 months (mo) (CI 95% [34.0-47.6]): 51.9 mo [43.0-62.3] for the RT group and 30.7 mo [23.3-37.8] for the surveillance group (Surv). None of the pts developed metastasis during follow-up. With 23 LR, 4 in the RT group and 19 in the Surv group, 3-years LRF rates were 98.8% [91.8-99.8] vs 90.4% [82.3-95.0] with and without adj RT (p<0.001). Once stratified on time period (before/after 2003), adj RT, age and margin resection (R0 vsother) were independently associated with LRFS. No OS difference was observed (p=0.151). Conclusions: In this study, adj RT following resection of ALT/WD-LPS was associated with a reduction of local recurrence risk. More prolonged and homogeneous follow-up is required to confirm these results.
Incidence of brain metastases and overall survival in patients with primary cardiac sarcoma: A retrospective case series.
Authors: Shango Maryann , Zhao Lili , Leja Monika , McHugh Jonathan B. , Schuetze Scott , Chugh Rashmi
Published: March 2020

10584

Background: Primary cardiac sarcoma (PCS) is the most common primary cardiac malignancy, but is a rare primary site of sarcoma. We present 21 cases from a tertiary care center to better understand this uncommon malignancy. Methods: A cancer center-based registry and pathology database were searched to identify pts diagnosed with PCS from 1992-2013 at University of Michigan. Kaplan-meier method was used to estimate survival. Cox proportional hazard model was used to associate variables to occurrence of metastases (mets) or death. Results: Atotal of 21 pts (F12, 9M) with PCS were identified, median age 36 (range 11-74). The most common presenting symptoms included dyspnea (16) and chest pain (6; 5 with associated pericardial effusion). Histologies included: angiosarcoma (9), leiomyosarcoma (4), undifferentiated pleomorphic (3), spindle cell (2), fibrosarcoma (1), rhabdomyosarcoma (1) and synovial (1). Sites of origin were R atrium (7), R ventricle (2), L atrium (10) and pericardium (2). Ten pts presented with mets; most common sites were lung (8), liver (2), brain (2), pancreas (2) and bone (2). Surgery was attempted in 12 pts, achieving 1 R0 resection. Pts received a median of 1 (0-7) systemic therapies. Median overall (OS) was 12.6 mos (range 3-79) from diagnosis. Pts without prior surgery were more likely to have mets or death (p=0.038). Brain mets were common, occurring in 7 of 21 pts after a median of 7 mos (range 1-75) from diagnosis. Median OS after diagnosis of brain mets was 8 mos. Of the 7 pts who developed brain metastasis, 5 had PCS originating in the left heart. Of the 2 pts with PCS in the right heart, one was evaluated for and had a right to left shunt. The likelihood of developing brain mets did not correlate with age, chemotherapy, or surgery. Conclusions: PCS portends an extremely poor prognosis, marked by inability to achieve complete resection and a high incidence of disseminated disease at diagnosis. Metastatic disease to the brain was much more common in PCS (33%) as compared to STS of any origin (approximately 1-8%), particularly in pts with PCS originating in the left heart. Clinicians should have a low threshold for brain imaging evaluation of PCS pts.
A phase II trial of novel anthracycline amrubicin in advanced soft tissue sarcoma.
Authors: Gouw Launce , Randall R Lor , Jones Kevin , Chawla Sant P. , Sharma Sunil
Published: March 2020

10587

Background: Amrubicin is a 9-aminoanthracycline with significantly less cardiotoxicity than doxorubicin, a current standard against soft tissue sarcoma, and may represent an appealing alternative first line therapy. We report findings in a phase II study investigating tolerability and efficacy of amrubicin in patients with advanced STS. Methods: We enrolled adult patients in a single-arm open label study with locally advanced or metastatic soft tissue sarcoma, no prior systemic treatment, measurable disease, an ECOG PS <2, and adequate organ function. We administered amrubicin (40 mg/m2 IV over 10’) on D#1-3 of a 21D cycle with GCSF support. Six cycles were planned with continuation at clinician discretion. We used RECIST 1.1 to radiologically assess response to therapy. Toxicities were assessed using CTCAE 4.0. The primary objective was overall response rate (CR+PR), and clinical benefit (CR+PR+SD). We employed a 2- stage design, with 15 patients treated in the first stage. Error rates were α=5% for accepting a poor regimen and β=10% for rejecting a promising regimen, with planned enrollment of 30 patients through the second stage if activity was observed. Results: 15 of 15 planned patients enrolled in the first stage of this phase II clinical trial; 10 males and 5 females, with median age 59 (range 30-73). Of the 13 evaluable patients, at 6 cycles 3 patients achieved a PR, with best response of 78% reduction of target lesions; 4 patients demonstrated minor response/stable disease (SD), ranging from 11-28% reduction of target lesions, and 4 patients had minor progression/SD (less than 20% progression). Two patients progressed >20%. Clinical benefit is currently 85.7% (12/14). Amrubicin has been well tolerated, with primarily grade I and II AEs. A single dose adjustment has occurred but no treatment delays. No cardiac complications, ECG or significant echocardiogram changes have been noted. Conclusions: Amrubicin is a novel anthracycline with encouraging activity against STS and an extremely well tolerated side effect profile. Further study of amrubicin in STS is warranted. With minor treatment-related morbidity, amrubicin would also be a good candidate for combination therapy with other standard or experimental therapeutics. Clinical trial information: NCT01259375.
Copy number changes in triple-negative breast cancer: New molecular targets.
Authors: Koudelakova Vladimira , Radova Lenka , Svoboda Marek , Wei Wenbin , Kharaishvili Gvantsa , Bouchal Jan , Trojanec Radek , Hajduch Marian , Kolar Zdenek , Bouchalova Katerina
Published: March 2020

1063

Background: Triple negative breast cancer (TNBC) is associated with tumor aggressiveness and high recurrence rate. Treatment options are limited due to lack of molecular-genetic markers and targeted therapy. The aim of our research is assessment of copy number changes in TNBC patients and identification of potential markers for personalized therapy. Methods: Fresh-frozen tumor tissues were collected from 148 patients with TNBC stage I-III. Genomes of these samples were profiled by Affymetrix SNP6.0 arrays. Arrays were normalized using R/Bioconductor and GISTIC 2.0 was used to identify copy number changes. Results: TNBC showed a high level of chromosomal instability and heterogeneity. More than 200 significantly altered chromosomal regions (q value < 0.25) were identified with frequency from 7.4 to 48% cases. Amplification of cell proliferation regulators (MYC, FGFR2, cyclins E1 and E2, PIK3CA, NFIB), regulators of vascularization (VEGFA) and epithelial–mesenchymal transition (CAV1 and CAV2) were found with high significance (q value < 0.1). Deletions of CDK regulators CDKN2B and CDKN2A, and tumor suppressors PTEN, RB1, APC and POT1 were also detected with highly significant q value < 0.1. Importantly, novel copy number changes of genes influencing inflammation, expression regulation and chromatin modification, localized on 1q, 7p, 8q, 9p, 17q and 19p, were found in more than 15% of samples. Conclusions: Despite the fact that TNBC is a heterogeneous group, several common copy number changes were identified. Our analysis confirmed copy number changes of important known genes as well as identified novel markers involved mainly in inflammatory and regulatory processes which could be targets of future therapies. Grant: Biomedreg CZ.1.05/2.1.00/01.0030.
Differential changes in tissue biomarkers after bevacizumab (BEV) alone in a neoadjuvant study of BEV and chemotherapy in ER+ breast cancer (BC) versus triple-negative breast cancer (TNBC) patients (pts).
Authors: Boucher Yves , Martin John D. , Tolaney Sara M. , Ancukiewicz Marek , Seano Giorgio , Goel Shom , Yeh Eren , Meyer Jack E , Isakoff Steven J. , Duda Dan G. , Winer Eric P. , Krop Ian E. , Jain Rakesh K.
Published: March 2020

1065

Background: The benefit of the anti-VEGF antibody BEV—despite its confirmed activity with chemotherapy—remains unclear in BC pts. This may reflect that its benefit is limited to an unknown subset of BC pts. Methods: We previously reported the outcome and circulating biomarker data of a phase II study of neoadjuvant BEV with chemotherapy in ER+ BC and TNBC pts (NCT00546156; ASCO 2012 abstr 1026). In the present study we evaluated tissue biomarkers after 1 run-in cycle of BEV treatment alone. Patients then received BEV with standard dose-dense doxorubicin/cyclophosphamide/paclitaxel. We analyzed the changes in tissue biomarkers in ER+ BC versus TNBC pts after BEV alone and their correlation with outcome at surgery. The primary endpoint was pathologic response, measured by the Miller-Payne (MP) score (MP5=pCR). Results: Mean MP score was 3.1 for ER+ BC pts versus 4 for TNBC pts (area under ROC=0.60, P<0.001). This supports the hypothesis that the activity of BEV with chemotherapy may depend on BC subtype. In TNBCs, BEV significantly decreased mean microvascular density (MVD) by 33% (p<0.05). MVD was inversely correlated with the fraction of tissue positive for the hypoxia marker CAIX post-BEV (p<0.01). Moreover, a high pre-treatment MVD correlated with an increase in CAIX+ fraction post-BEV (p<0.05). In addition, a drop in MVD associated with increased CAIX+ fraction post-BEV (p=0.05). Finally, high (>60%) pericyte coverage post-BEV—ie, more mature vessels—was inversely correlated with CAIX+ fraction (p<0.05). MP score was more favorable for TNBC pts with lower CAIX+ fraction at baseline (p=0.058) and post-BEV (p<0.05), and higher MVD at baseline (p<0.05) and post-BEV (p<0.05). In contrast, BEV reduced MVD non-significantly by 15% in ER+ BC (p=0.25). There was no correlation between MVD and CAIX+ fraction in ER+ BCs. In contradistinction to TNBC, in ER+ BCs the fraction of CAIX+ tumor was directly correlated with MP score (p<0.01). Conclusions: Our exploratory study suggests that vascular pruning post-BEV may reduce vascular function and increase hypoxia, and reduce the effectiveness of chemotherapy in TNBC. Clinical trial information: NCT00546156.
Development and validation of a model and web application to predict 5-year distant relapse-free survival in women receiving neoadjuvant chemotherapy.
Authors: Mohiuddin Jahan , Deal Allison Mary , Drobish Amy , Cheang Maggie Chon U. , Reeder-Hayes Katherine Elizabeth , Carey Lisa A.
Published: March 2020

1077

Background: Response to neoadjuvant chemotherapy (NAC) is an increasingly recognized intermediate marker for prognosis, but we still lack validated prognostic tools that incorporate tumor factors and response. This study aimed to create a prognostic model and nomogram for 5-year distant relapse-free survival (DRFS) and to develop a web application for providers and patients to predict the probability of distant relapse within 5 years. Methods: The prognostic model was developed using data from patients treated with NAC in the UNC Neoadjuvant Database and the Cox proportional hazards method. Patients who received NA trastuzumab were included in model data, but patients who received NA endocrine therapy were not included. The model was internally validated with bootstrap resampling, and externally validated with an independent, public data set (n=411) (Cancer Res 2011;71(24 Suppl):Abs S5-2). A web tool was developed to calculate probability of 5-year DRFS. Results: Four-hundred and seven stage I-III patients, including 106 relapse events, were used for model development. The following factors were ultimately included in the model: RCB class, age, overall grade, HER2 status, hormone receptor (HR) status, and an interaction term between age and HR status. Validation showed agreement between predicted and observed outcomes in all patients and more specifically HR+/HER2- and HR-/HER2- patients (Table). There were an insufficient number of HER2+ patient in the validation data to reliably analyze that subgroup. Conclusions: An externally validated predictive modelincorporating patient, tumor, and response variables is accurate in predicting 5-year distant relapse risk for patients undergoing NAC. The model can be conveniently accessed as an online application at www.NeoadjuvantRelapse.info for precise risk prediction. [Table: see text]
Safety and tolerability of adjuvant dose dense chemotherapy in elderly patients with node-positive early breast cancer.
Authors: Karavasilis Vasilios , Pectasides Dimitrios G. , Papadimitriou Christos A. , Gogas Helen , Kouvatseas George , Christodoulou Christos , Koutras Angelos , Pentheroudakis George E. , Linardou Helena , Razis Evangelia , Aravantinos Gerasimos , Dimopoulos Meletios A. , Fountzilas George
Published: March 2020

1093

Background: Intensive chemotherapy confers benefit to older and younger patients with early breast cancer (BC). We aim to characterize the feasibility and toxicity profile of adjuvant dose-dense chemotherapy (ADDC) in older women with early node positive (BC). Methods: Available data from women who received ADDC for BC within three randomized trials between 1997 and 2008 were retrieved from our electronic database. These trials included HE 10/97: epirubicin and cyclophosphamide, methotrexate and fluorouracil (CMF) with or without paclitaxel, HE 10/00: epirubicin and concurrent or sequential paclitaxel and CMF and HE 10/05: a sequential three arm study of epirubicin, paclitaxel and CMF compared with epirubin, CMF and either weekly paclitaxel or docetaxel. We identified women aged >65 years and we looked at differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome. Results: From a total of 2,640 patients with a median age of 52 years, who received ADDC, we identified 453 patients (17%) > 65 years, hormonal positive in 76%, all node negative. At least 90% of the planned doses were delivered in 37% of the elderly, compared to 49% of the younger patients (p < 0.0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients compared to 21% of younger (p < 0.0001). Febrile neutropenia occurred in 4.5% of elderly patients as opposed to 2% of younger (p < 0.002). Elderly patients experienced more frequently grade 3 and 4 fatigue, mucositis and sensory neuropathy, though the incidence of these toxicities was relatively low (all p < 0.0001). Relative dose intensities were significantly lower in elderly patients, mainly affected docetaxel and paclitaxel administration. Treatment discontinuation, regardless causality, was not different in both groups. At a median follow-up of 120 months, there was no significant difference in disease free survival. Conclusions: Elderly node positive BC patients treated with ADDC derive comparable clinical benefit as younger patients, mainly in the cost of increased risk of hematological toxicity. This should be taken into account in decision making and treatment individualization in high risk BC patients.
Prognostic impact of changes in circulating tumor cells (CTC) in metastatic breast cancer (MBC).
Authors: Wallwiener Markus , Hartkopf Andreas D. , Riethdorf Sabine , Sprick Martin , Domschke Christoph Wolfram , Schott Sarah , Baccelli Irene , Modugno Caroline , Schoenfisch Birgitt , Burwinkel Barbara , Marme Frederik , Heil Joerg , Sohn Christof , Pantel Klaus , Trumpp Andreas , Schneeweiss Andreas
Published: March 2020

11012

Background: To prospectively assess the prognostic value of CTC counts at baseline and after one cycle of therapy and their kinetics for response, progression-free (PFS), and overall survival (OS) in MBC. Methods: MBC patients underwent CTC enumeration (CellSearch, Veridex) at baseline (CTCBL), after one cycle of a new line of therapy (CTC1C), and at progression (CTCPD). CTC status was classified as negative (neg (−)) or positive (pos (+)) for <5 and ≥5 CTC/7.5 ml peripheral blood, respectively. CTC kinetics (CTCKIN) from CTCBL to CTC1C were classified as favorable if CTCs remained neg (neg>neg) or became neg (pos>neg), or as unfavorable (neg>pos or pos>pos). Tumor response was assessed every 2–3 months using RECIST criteria. CTC status and kinetics were associated with outcome using log-rank and Fisher’s exact tests. Results: Of 326 patients enrolled (median age (range) at first diagnosis: 50 (23–81) years), 115/326 (35%) were CTCBL+, 51/162 (31%) were CTC1C+, and 39/108 (36%) were CTCPD+. Median follow-up was 15.9 months (mos). Median PFS and OS were significantly reduced in CTCBL+ compared to CTCBL− patients (PFS, 4.3 vs. 7.1 mos, p = .019; OS, 15.0 mos vs. not reached (nr), p <.001) and for CTC1C+ compared to CTC1C− patients (p <.001 for PFS and OS). CTCKIN were predictive of progressive disease as best response (neg>neg, 33%; pos>neg, 38%; pos>pos, 60%; neg>pos, 75%; p = .040). PFS and OS for patients with unfavorable CTCKIN were significantly shorter than for favorable CTCKIN (PFS, 3.7 vs. 6.8 mos, p <.001; OS, 7.8 mos vs. nr, p <.001). Conclusions: CTC at baseline, CTC after one cycle and CTC kinetics are highly predictive of outcome in MBC. Serial CTC enumeration could serve as a useful adjunct to standard diagnostic tests in tailoring therapy. Further details of CTCPD will be presented at the meeting. Clinical trial information: S-295/2009.
Elevated CSF-1 serum concentrations to predict lymph node metastasis and overall survival in women with early breast cancer.
Authors: Singer Christian F. , Aharinejad Seyedhossein , Salama Mohamed , Zins Karin , Paulus Patrick , Berger Andreas
Published: March 2020

11032

Background: Colony-stimulating factor-1 (CSF1) is a key modulator of tissue macrophages and contributes to the physiological function of the mammary gland. It has, however, also been associated with breast cancer since expression of its receptor CSF-1R is a strong predictor of poor outcome in early breast cancer and results in tumor cell invasiveness and pro-metastatic behavior in vitro. Methods: We have prospectively measured circulating CSF-1 with ELISA in 572 women with early breast cancer and in 688 women with benign breast lesions; and correlated these values with overall survival, nodal status and other clinical and histological parameters. Results: Serum CSF-1 concentrations were significantly elevated in patients with early breast cancer when compared to those with benign tumors (p<0.0001). Within breast cancer patients, CSF-1 was higher in women with involved axillary lymph nodes (p=0.04). CSF-1 concentrations were correlated with tumor size (p=0.002), age (p<0.001), and Ki67 expression (p=0.006). Log CSF-1 serum concentrations were predictive of poor survival in both univariate (HR: 3.77, CI: 1.65-8.65, p=0.002) and multivariate analyses (HR: 3.1, CI: 1.03-9.33, p=0.04). Post- but not premenopausal women with CSF-1 serum concentrations >873 pg/ml experienced a significantly poorer outcome (p=0.004 log rank test). Conclusions: CSF1 serum concentrations are elevated in women with malignant breast tumors. In early breast cancer, elevated serum CSF-1 is associated with nodal involvement, and in postmenopausal women also with poor overall survival.
Effect of nonmalignant accessory cells from the metastatic microenvironment on breast cancer cell resistance to antiestrogens.
Authors: Dhimolea Eugen , Mitsiades Constantine S.
Published: March 2020

11039

Background: To address the role of the local metastatic microenvironment in the antiestrogen (AE) resistance exhibited by disseminated breast cancer (BrCa), we assembled heterotypic in vitro three-dimensional (3D) tissue cultures comprised of estrogen receptor-positive (ER+) BrCa cells and non-malignant accessory cells from organs frequently targeted by metastatic disease, to model the composition and architecture of metastatic lesions. Methods: MCF7 cells expressing luciferase, cultured alone or with accessory cells, were exposed to dose-ranges of hydroxytamoxifen (4-OHT), fulvestrant or raloxifene. MCF7 cells were also injected s.c. in nude mice either alone or with HS-5 bone marrow stromal cells (BMSCs). Tumor spheroid viability or xenograft growth were measured by bioluminescence. Results: MCF7 response to AEs in 3D conditions (collagen type I and/or Matrigel) was marked by acinar differentiation of tumor spheroids that resembles normal breast epithelium. Co-culture of MCF7 and immortalized accessory cells from the bone (BMSCs; HOBIT and hFOB osteoblasts), brain (SVGp12 astrocytes), liver (THLE3 hepatocytes), and lung (MRC9 fibroblasts) in 3D (but not 2D) conditions, conferred resistance to 4-OHT, raloxifene, and fulvestrant at clinically relevant doses. Heterotypic xenografts (MCF7 + BMSCs) had reduced response to tamoxifen compared with monotypic xenografts (MCF7 alone). BMSCs induced in MCF7 cells downregulation of TGFβ2; upregulation of a transcriptional signature enriched for genes associated with high-grade tumors, including genes involved in interferon response, signaling through EGFR superfamily members, NFkB and other antiapoptotic pathways; and elevated c-Myc protein levels. Exogenous TGFβ2 or neutralizing antibodies against INFγ partially re-sensitized MCF7 cells to 4-OHT in co-cultures. Conclusions: Our results indicate that accessory cells representing the microenvironment of metastatic sites confer AE resistance to BrCa cells in 3D tissue cultures and xenograft models. The mechanisms of stroma-induced AE resistance may reveal new therapeutic targets for refractory BrCa patients with metastatic disease.
Circulating tumor cells as a prognostic marker in metastatic non-small-cell lung cancer patients receiving chemotherapy.
Authors: Sakamori Yuichi , Kim Young Hak , Yoshioka Hiroshige , Hirabayashi Masataka , Onaru Koichi , Fukui Motonari , Hirata Toshiki , Mishima Michiaki
Published: March 2020

11041

Background: Radiographic response remains the gold standard for assessment of the chemotherapy effect and has been used as a surrogate endpoint in clinical trials. Recently, circulating tumor cells (CTC) have emerged as a novel prognostic marker in many types of cancer; however, their significance has not been fully examined in patients with non-small-cell lung cancer (NSCLC). Methods: We conducted a prospective study to evaluate the clinical significance of CTC in metastatic NSCLC patients treated with chemotherapy. Peripheral blood samples were collected for CTC analysis before chemotherapy, after 1 cycle of chemotherapy, and after 2 cycles of chemotherapy. CTC analysis was performed using CellSearch (Veridex). Results: One hundred and forty-eight patients wereenrolledbetween August 2009 and January 2012, and 121 patients were eligible for the analysis. CTC was positive (CTC ≥1) in 30.6% (37/121) before chemotherapy, in 21.0% (26/118) after 1 cycle of chemotherapy, and in 21.6% (24/111) after 2 cycles of chemotherapy, respectively. CTC counts were higher in patients with N3 lymph node metastases (vs. N0-2, p = 0.0001), M1b status (vs. M1a, p = 0.0081) or ≥2 metastasis sites (vs. 1 metastasis site, p = 0.0342). Although not statistically significant, a positive trend was observed between the radiographic response and the dynamic change of CTC counts (p = 0.0734). In multivariate analysis, including the radiographic response (responder vs. non-responder), baseline CTC was a significant negative predictive factor for PFS (HR = 1.867; p = 0.0080) and OS (HR = 2.753; p = 0.0006). Considering pre- and post-treatment time points (before and after 2 cycles of chemotherapy) together, CTC-positive patients at either time point experienced significantly worse PFS (HR = 1.747; p = 0.0143) and OS (HR = 2.031; p = 0.0123) than those who were CTC negative at both time points. Conclusions: CTC was an independent prognostic factor in patients with metastatic NSCLC who was treated with chemotherapy.