bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of neoadjuvant imatinib therapy of patients with primary locally advanced GIST.
Authors: Arkhiri Peter , Poddubnaya Irina , Nered Sergey N. , Peregorodiev Ivan N. , Nikulin Maxim P. , Stilidi Ivan S.
Published: September 2018

11037

Background: percutaneous biopsy of gastrointestinal tumors is contraindicated, that is why prospective randomized trials of efficiency of preoperative imatinib therapy weren't conducted. According to the results of theRTOG S-0132/ACRIN 6665, CST1571-BDE43 and other studies, neoadjuvant imatinib therapy increase tumor resectability and improve progression-free and disease-specific survival. The optimal timing of surgical intervention is likely during the maximal response on treatment (6 to 12 months as a rule). Methods: We have analyzed the treatment results of 86 patients with locally advanced GIST which were treated since January 1st 2002 till 20 January 2016 at N.N. Blokhin Russian Cancer Centre. The primary tumor was located in the stomach - 32 pts (37,2%), duodenum and small bowel - 37 (43,1%), other (colon, rectum and extraorgan) – 17 pts ( 19,7%). The median follow-up time was 4.9 years. There are 4 groups in the trail: group 1 - 29 patients received only surgical treatment, group 2 - 12 pts– surgical resection with adjuvant imatinib therapy for 1 year; group 3 - 25 pts – adjuvant imatinib therapy for 3 years and group 4 - 17 pts– surgical resection with neoadjuvant and adjuvant imatinib therapy (1 - 3 years). The remained 3 patients received surgical resection with adjuvant imatinib therapy for 5 years. Results: Survival analyses showed a significant improvement of RFS and OS in patients who received combined treatment with neoadjuvant and adjuvant imatinib therapy. The five-year RFS in first group of patients was 10,8%, in 2 group - 16,7%, in 3 group - 68,4%, and 4 group - 79,8% (p = 0.0001). The 5-year overall survival in these groups was 42,6%, 66,7%, 76,1% and 91.6% ( p = 0,0072) respectively. In the patients with 5-years adjuvant therapy, diseases progression was not noted. During neoadjuvant therapy disease progression has been registered in two patients. The median time of preoperative imatinib therapy was 11 month (from 3 to 24 month). Neoadjuvant imatinib therapy increased the rate of R0 (14 pts – 82,4%) and organ-sparing (12 pts – 70,6%) resections. Conclusions: The optimal approach in patients with locally advanced GIST is combined surgical treatment with neoadjuvant and adjuvant (at least for 3 years) imatinib therapy.
Rechallenge in advanced GIST progressing to imatinib, sunitinib and regorafenib: An Italian survey.
Authors: Vincenzi Bruno , Nannini Margherita , Grignani Giovanni , Fumagalli Elena , Gasperoni Silvia , D'Ambrosio Lorenzo , Badalamenti Giuseppe , Dei Tos Angelo Paolo , Incorvaia Lorena , Casali Paolo G , Santini Daniele , Tonini Giuseppe , Stellato Marco , Catania Giovanna , Spalato Ceruso Mariella , Pantaleo Maria A.
Published: September 2018

11038

Background: We retrospectively collected data from metastatic Italian GIST patients treated with imatinib or sunitinib reintroduction after progression to conventional three or four lines of therapy. Methods: 82 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected in the present analysis from 6 cancer centres. All patients received all three standard kinase inhibitors. Imatinib dose increase as active second line or 800 mg upfront in exon 9 mutant GIST were allowed. Specific mutations were recorded if available (deletion versus others) and correlated with survival and response according to RECIST 1.1 or CHOI criteria. Results: Seventy-four of 82 patients received Imatinib 400 mg as rechallenge, while 8 patients were treated with sunitinib at personalised dose and schedule according to the physician’s choice. Mutational status was available in all patients and in 68 patients details about type of mutation were achievable. The median follow-up was 13 months (range 1-42 months). The median time to progression (TTP) in patients receiving a rechallenge therapy was 5.4 months (95% CI 1.9-13.5) and Overall Survival (OS) was 10.6 months (95% CI 2.8-26.9). Apparently, in this setting a correlation between mutational status and response rate, TTP or OS was not found. On the contrary, considering only exon 11 mutated patients and comparing patients with deletion vs non deleted ones a significant difference was identified both in terms of TTP and OS (respectively, P = 0.04 and P = 0.02). Conclusions: Our retrospective data confirm that the rechallenge of imatinib or sunitinib is a reasonable option in advanced GIST patients after failure of previous treatments. As expected, imatinib is the most frequently prescribed option in the Italian real-life setting, demonstrating a TTP and OS longer than those observed in previous studies. Also the prognostic value of the specific type of exon 11 KIT mutations has been confirmed in our series.
Prognosis of desmoid tumors (DT): A prospective nationwide survey of 771 patients (pts).
Authors: Ryckewaert Thomas , Le Cesne Axel , Bonvalot Sylvie , Blay Jean-Yves , Giraud Antoine , Bompas Emmanuelle , Rios Maria , Salas S Bastien , Isambert Nicolas , Boudou-Rouquette Pascaline , Honoré Charles , Italiano Antoine , Ray-Coquard Isabelle Laure , Piperno-Neumann Sophie , Gouin Francois , Bertucci Francois , Ducimetiere Francoise , Coindre Jean-Michel , Penel Nicolas
Published: September 2018

11047

Background: Prognostic factors and optimal management of DT are not yet established. Methods: We analyzed the outcome of 771 consecutive DT pts treated between 01/2010 and 12/2016 in France. We have calculated event-free survival (EFS) defined as local relapse after surgery, progressive disease during non surgical approach or change in treatment strategy (e.g. from wait and see to systemic treatment or local treatment). Results: The sex ratio M/F was 219/552, the median age was 39 (2-90), and the median size 57 mm (4-700). 596 DT are found CTNNB1-mutated (71%). The 1st treatment was wait and see (369, 48%), surgery (343, 44%), systemic treatment (25, 3%), or radiotherapy (3, 0%). The median follow-up was 32 mo. 230 events occurred (including 1 death). The median EFS was 27 mo. After initial wait and see, pts required systemic treatment in 61 cases (15%), radiotherapy (4; 1%), cryotherapy (3; 1%), surgery (2; 0%) and radiofrequency (1, 0%). After initial surgery, DT pts required wait and see for relapse in 88 cases (25%), systemic treatment in 17 cases (5%), radiotherapy (6; 2%), cryotherapy (2; 0%) and surgery (1, 0%). Univariate analysis identified 3 factors associated with EFS: favorable locations (median not reached (NR) vs. 21 mo; p = 0.0001), nature of sampling (core needle biopsy: 31 mo; resection 26 mo and open biopsy 15 mo, p = 0.046) and superficial DT (NR vs. 28 mo, p = 0.00001). Favorable locations included: abdominal wall (236 pts), intra-abdominal (78 pts), breast (27 pts) and digestive viscera (42 pts). Chest wall (209 pts), head and neck (28 pts), lower limb (90 pts), upper limb (25 pts) and pelvis (18 pts) were all associated with poor EFS. Multivariate analysis identified only 1 prognostic factor for EFS: favorable location HR = 0.52 [0.39-0.69]. Compared to surgery, wait and see as 1st treatment was associated with better EFS in unfavorable DT locations (HR = 0.74 [0.74-0.56]; p = 0.001) but not associated with EFS in favorable locations (HR = 0.89 [0.69-1.13]; p = 0.420). Conclusions: Since primary location of DT is the major determinant of DT outcome, stratified approach according to location has to be prospectively assessed. Correlative biology analyses are warranted to better understand these findings.
Effects of temozolomide and bevacizumab in relapsed patients with heavily pretreated uterine leiomyosarcoma.
Authors: Matsuura Hiroko , Ikeda Sayaka , Kudoh Kazuya , Sasaki Naoki , Takano Masashi , Goto Tomoko , Kikuchi Ryoko , Kita Tsunekazu , Sakamoto Masaru , Aoki Daisuke , Susumu Nobuyuki , Kouta Hiroko , Kikuchi Yoshihiro
Published: September 2018

11056

Background: Uterine leiomyosarcomas (ULMs) tend to recur regardless of their stage, and there is no satisfactory report for relapsed ULMs. Temozolomide (T) is derivatives of dacarbazin and these agents have been used for treatment of ULMs. ULMs has a plenty of vessels compared to uterine myoma so that bevacizumab (B) was used in ULMs. In the present study, we evaluated the effect of TB in heavily pretreated relapsed ULMs. Methods: From 2009 to 2016, total 19 patients (pts) with heavily pretreated ULMs were enrolled. Patients were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Treatment was continued until disease progression and/or unmanageable toxicities. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) v1.1, and adverse effect (AE) was assessed by common terminology criteria for adverse events (CTCAE) v4.0. Results: Seventeen of 19 pts were subjected to response evaluation. Median age of pts was 56.3 years (range: 31-69). Three pts (18%) had complete response (CR), 2 (12%) had partial response, and 7 (41%) had stable disease (SD). The response rate (RR: CR+PR) and clinical benefit rate (CBR: CR+PR+SD) were 29% and 71%. The median progression-free survival was 14.2 months (range: 0-89). Median administration cycle was 9.5 (range: 2-48). AE with grade 3 and more over were observed in 6 pts. There was one dead case from perforation, but toxicity was almost manageable. Conclusions: We experienced 3 cases of CR, and two of them had CR for more than two years. Intriguingly, TB could be substantially effective even in relapsed patients with heavily pretreated ULMs. These results warrant further prospective and randomized studies.
Immunoprofiling in alveolar soft part sarcoma.
Authors: Salah Samer , Lewin Jeremy Howard , Davidson Scott , Anderson Nathaniel , Periera Sergio L , Lau Beatrice , Shlien Adam , Dickson Brendan , Ferguson Peter , Wunder Jay , Abdul Razak Albiruni Ryan
Published: September 2018

11059

Background: Alveolar Soft Part Sarcoma (ASPS) is a distinctive tumor characterized by a canonical ASPL-TFE3 fusion. Treatment options are limited. We assessed tumor immune cell infiltrates, and correlated this with patients receiving PD-1 blockade. Methods: A retrospective institutional review was performed for 18 cases of ASPS. Immunohistochemistry was performed on paraffin-embedded tissue (PET) for T-lymphocyte markers (CD3/CD4/CD8), and PD-1/PD-L1 (Ventana). Expression was quantified by standard methods: (total cells per high power field: score; 0:0; 1-10:1; 11-50:2; 50-99:3; 100:4). Select cases underwent DNA sequencing analysis using whole exome (WES, > 80X, n = 4) and genome (WGS, > 30X, n = 1) sequencing. Indel analysis was conducted via mutect2 ( > 5% variant allele frequency) and mutational signature was performed using deconstructSigs. Results: The median age was 27 (15-54). Disease status at diagnosis was: 44% localized; 56% metastatic. The median overall survival was 17 yrs (2.9-31). Four patients (pts) received immunotherapy with PD-1 blockade with 1 complete response (CR), 2 durable partial responses (PR) and 1 stable disease (SD). PET was available in 12 cases. PD-1/PD-L1 expression (≥1) was seen in 50% and 17%, respectively. Composite CD3, CD4 and CD8 infiltration were 2, 1, and 1, respectively. Patients with CR/PR to PD-1 blockade (n = 3) had no clear correlation with PD-1, PD-L1 or lymphocyte markers. Exomic characterization (n = 4) demonstrated no clear excess mutation burden compared to Ewing sarcoma (5.7 vs 6.4 mut/MB). Mutational signatures via COSMIC were identified in the mismatch repair (MMR) pathway in 2 of 4 cases (Pt A: Signature (S) 26; pt B: S6 and S15). Pt B also underwent WGS which confirmed a COSMIC signature in the MMR pathway. Indel analysis did not confirm aberrations in standard MMR or polymerase genes. Conclusions: Preliminary findings suggest activity with PD-1 blockade in ASPS; however, this does not appear to correlate with tumour-infiltrating T lymphocytes. Genomic analysis suggests an MMR signature may account for these responses, but standard MMR aberrations were not identified. Further validation is underway.
Trabectedin for advanced soft tissue sarcoma: Ten-year real-life perspective.
Authors: Shamai Sivan , Merimsky Ofer
Published: September 2018

11060

Background: Trabectedin is a marine - derived chemotherapy, which lately received FDA approval for use in anthracycline resistant advanced soft tissue sarcoma (STS), especially liposarcoma and leiomyosarcoma (L-sarcomas). Methods: We report our ten-year real-life experience with trabectedin, 1.5mg/m2/d c.i.v. q3w till progression, regarding safety and efficacy in a cohort of 86 patients (24-83y). Liposarcoma was the diagnosis in 46% , leiomyosarcoma in 43%. Results: A total of 703 cycles of Trabectedin were given, with a median of five cycles per patient (range 1-59). Median overall survival (mOS) was 11 months for liposarcoma patients (range 1-63), and 15 months for leiomyosarcoma patients (range 1-35). There was no statistically significant difference in progression free survival (PFS), when stratified according to previous treatment lines given. Trabectedin exhibited a favorable safety profile, with only 22% requiring dose reductions. Grade 3 and more toxicity were noted in 25% of the patients, mostly myelosuppression. There was no treatment related death. Conclusions: In contrast to former trials, our retrospective data represents real life experience with Trabectedin, and includes patients with diverse age, histology, performane status, prior treatments and tumor burden. The group includes 10 patients (11.6%) who received Trabectedin as first line (Either due to congestive heart failure or to rapid progression following adjuvant Doxorubicin and Ifosfamide), 10 patients (11.6%) were above age 70, nine (10.5%) had histologies other than liposarcoma or leiomyosarcoma, and 23 (26.7%) had ECOG PS of 2 or higher. Trabectedin is a safe and effective drug in advanced high grade STS. Further research is needed to identify which patients will benefit most.
Circulating cell free tumor DNA detection as novel biomarkers to monitor desmoid tumors evolution.
Authors: Salas S Bastien , Macagno Nicolas , Penel Nicolas , Duffaud Florence , Nanni Isabelle , Bouvier Corinne , Rouah Raquel , Ouafik L'houcine , Bouhadiba Toufik , Bonvalot Sylvie , Fina Frederic
Published: September 2018

11063

Background: Since desmoid tumors (DT) exhibit an unpredictable clinical course, with stabilization and/or spontaneous regression, an initial “wait-and-see” policy is the new standard of care to select best indications of active treatments in case of significant evolution. Therefore, translational research is crucial to identify predictive factors of progression. Most DT are characterized by CTNNB1 mutation (CM) in exon 3 (T41A, S45F, S45P). Circulating cell-free tumoral DNA (ctDNA), named "liquid biopsy", has emerged as a new promising non-invasive tool to detect biomarker in several cancers. Methods: We present a method of detection of DT-specific CM using a targeted strategy digital droplet PCR (ddPCR) on cell-free DNA (cfDNA) extracted from blood samples of 31 DT patients (pts). T41A, S45P, S45F and their respective CTNNB1 wild-type probe were designed for ddPCR. Furthermore, we analyzed the correlation of cfDNA levels (CTNNB1 wt/ml plasma) and evolution of the tumor. Results: Initial DT CM statuswas known for 28 pts and unknown for 3 pts. 24 pts presented a CM (17 pts T41A, 6 pts S45F and 1 pt S45P), 2 pts a mutation of APC, 2 pts were wild-type, and 3 pts were undetermined. Among pts with a CM, CTNNB1 mutants were detected in the cfDNA of 6 patients (19.4%). CM detection was not correlated with the quantity of cfDNA analyzed (p = 0,7263–Mann-Whitney (MW)). Absolute quantification of cfDNA (CTNNB1 wt) normalized by mL of plasma displayed higher levels for patients with progressive DT (p = 0,0009 - MW), this difference of cfDNA quantity was also present between progressive, stable and self-regressive DT (p = 0,0012 - MW). A threshold of 875 CTNNB1 copies/mL predicted DT progression with a sensibility of 100% (CI95%: 59-100) and a specificity of 76.5% (CI95%: 50.1-93.2). Absolute cfDNA quantity was also higher in patients harboring multiple desmoids (p = 0.0292 - MW). Conclusions: The absolute quantification of normalized cfDNA is correlated with evolution of the disease, independently of the initial tumor type of CM. This study opens the perspective of using cfDNA as a genomic biomarker to assess the tumor dynamics at initial diagnosis, and to monitor treatment strategy in case of tumor evolution.
Potential therapeutic genomic alterations in desmoplastic small round blue cell tumor.
Authors: Xiu Joanne , Bulbul Ajaz , Rashad Sadaf
Published: September 2018

11066

Background: Desmoplastic Small Round Blue Cell Tumor (DSRCT) originates from a cell with multilineage potential. A molecular hallmark of DSCRT is the EWS-WT1 reciprocal translocation. Ewing’s and DSRCT are treated similarly due to similar oncogene activation pathways and DSRCT has been represented in very limited numbers in sarcoma studies. Methods: Thirty-five DSRCT tumors were tested with a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Specific tests performed included sequencing (NextGen), protein expression (IHC) and gene amplification (CISH or FISH). Tumor mutational load (TML) was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Molecular alterations were compared to 88 Ewing sarcomas (ES). Chi-square tests were used for comparison and statistical significance was determined as p < 0.05. Results: In the 35 DSRCT tumors, high expression of TOP2A were seen in 63%, TOPO1 in 63%, PTEN in 62%, androgen receptor (AR) in 59%, EGFR in 42% of tumors; low expression of TUBB3 was seen in 44%, MGMT in 45%, TS in 48%, RRM1 in 57% and ERCC1 in 76% of tumors. When compared to ES, no significant difference was seen in protein expressions with the exception of a significantly higher overexpressson of AR in DSRCT (59% vs. 3%, p = 1.7E-10) and TUBB3 (56% vs. 29%, p = 0.03). Tumor expression of PD-L1 (Ab: SP142) was not seen in the 4 DSRCT and 10 ES tested. NextGen revealed a TP53 mutation (7%) and a FOXO3 mutation (L382fs) in DSCRT, while 6 TP53 mutations (13%), 2 APC mutations (L1129S and I1307K), 1 BRCA1(c.301+1G > A) and 1 CTNNB1 (T41A) mutation were identified in ES. Tumor mutational load evaluated in the 3 DSRCT and 11 ES tumors averaged 6 and 5 mutations per megabase, respectively. Conclusions: Molecular profiling on 35 DSRCT tumors and comparison with Ewing’s sarcoma revealed low immunogenicity ( < 10 Mutations/MB) and low frequency of actionable mutations including PD-L1 in both tumor types. High AR expression could present as a potential therapeutic target for DSRCT while taxanes may be more effective in Ewing’s sarcoma compared to DSCRT based on TUBB3 expression. Genomic and Molecular assessment may help determine the ideal regimen that will help achieve maximal tumor debulking.
When to treat Kaposi’s Sarcoma? Paclitaxel survival benefit on classic versus AIDS/HIV-related subtypes.
Authors: Eyzaguirre Eduardo , Enriquez Daniel , De la Cruz Ku Gabriel Antonio , Castro Victor , Morante Zaida , Valdiviezo Natalia , Portillo Diana , Cuellar Ponce de León Luis Ernesto , Mas Luis , Gomez Henry Leonidas
Published: September 2018

11077

Background: Kaposi’s Sarcoma (KS) is a angioproliferative disease related to AIDS/HIV (AIDS-KS) or not (Classic, CKS). Treatment options are limited in low-income countries where taxanes represent a cost-effective alternative. Our aim was to compare overall response (ORR) of paclitaxel and progression free survival (PFS) and overall survival (OS) between KS subtypes. Methods: We reviewed 203 medical records from pts diagnosed between 2002-2014 at the Instituto Nacional de Enfermedades Neoplasicas (Peru). Survival differences were calculated by log-rank test in the univariate analysis and Cox regression analysis for prognostic factors. Results: From 203 pts, 85 had CKS and 118 AIDS-CK. Mean age was 67 and 36years in CKS and AIDS-KS, respectively. Most pts were males (84.7%), coinfections as tuberculosis (11.9%) were more frequent in AIDS-CK. In CKS pts, 80% debuted with localized elevated lesions at lower limbs, 16% were resected, 48% received RT and 29% paclitaxel. Among AIDS-KS, 37% had poor risk, 22% were diagnosed concurrently to HIV infection. 76.9% had generalized lesions with origin at lower limbs, 50.5% had +ve nodes and 19% visceral disease. 25.8% had Zubrod > 2 and mean neutrophil to lymphocyte ratio (NLR) was 3.5, CD4 count was lower in pts with recently diagnosis of AIDS/HIV (166 vs 268, p = 0.039) and no differences were noted on viral load (mean 233 411). 77.1% of AIDS-KS pts received ART and 56.8% paclitaxel. In AIDS-KS ORR was 77%(CR:52%, PR:22%) versus 86% in CKS (CR:43%, PR:43%). At 4.3year median follow-up, 3-year PFS and OS was 71% and 75% in AIDS-CK, while CKS had 78% and 79%, respectively. Paclitaxel was associated with better survival among AIDS-KS patients (PFS HR:0.41, 95%CI:0.2-0.7, p = 0.004 and OS HR: 0.37, 95%CI:0.1-0.7, p = 0.007), patients with Zubrod≤2 had more survival benefit. There was not survival benefit in CKS pts. At multivariate analysis, ART and paclitaxel were associated with favorable PFS and OS, while higher NLR and poorer status performance to worse outcomes in AIDS-KS pts. Conclusions: Paclitaxel is an effective alternative treatment for AIDS-KS, there was not survival benefit in CKS patients. Poorer status performance and higher NLR were associated to worse prognosis.
Cancer-associated macrophage-like cells as prognostic indicators of overall survival in a variety of solid malignancies.
Authors: Adams Daniel , Adams Diane K , Lin Steven H. , Cristofanilli Massimo , Bergan Raymond C. , Marks Jeffrey R , Martin Stuart S , Chumsri Saranya , Ho Thai Huu , Lapidus Rena G. , Tsai Susan , Tang Cha-Mei , Alpaugh R. Katherine
Published: September 2018

11503

Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell subtype commonly found in the peripheral blood of patients in all stages of solid malignancies and in a variety of cancer subtypes. However, while their biological association to cancer is being studied, their clinical utilization as it relates to cancer prognosis has not been evaluated. Methods: A two year prospective study was undertaken to evaluate the relationship of CAMLs and overall survival (OS) in 6 solid tumor types. The single blind multi-institutional study consisted of 269 stage I-IV patients; breast (n = 57), esophageal (n = 21), prostate (n = 43), pancreatic (n = 59), lung (n = 54), and renal cell (n = 35), in treatment (n = 134) and untreated baseline (n = 135). 7.5mL of whole blood was filtered by CellSieve microfiltration assay and CAMLs enumerated, as previously described. Patients were grouped by CAML number ( < 6 or ≥6) and by size ( < 49 or ≥50 µm) to evaluate hazard ratios (HR) by censored univariate & multivariate analysis. Results: CAMLs were identified in 93% of samples, averaging 8.2 CAMLs/7.5mL blood sample, and found in all 6 cancers at baseline and during treatment. Average CAML number was associated with disease stage and CAML positivity was 4.4 & 80% (Stage I), 4.7 & 93% (Stage II), 9.3 & 98% (Stage 3), 12.1 & 97% (Stage IV). Univariate analysis of patients (n = 269) stratified by ≥6 CAMLs had reduced OS (HR = 1.8, 95%CI 1.1-2.9, p = 0.03). Further, CAML size also had reduced OS in patients with ≥50 µm CAMLs (HR = 2.7, 95%CI 1.8-4.0, p < 0.0001). Conclusions: Our data suggests that in solid malignancies, CAML number and size appear to clinically correlate with OS in early and late stage disease. Given these results relating CAMLs with OS, further analysis is warranted to determine if CAMLs can serve as a clinically-relevant blood-based marker.
VEGFR2 cytoplasmic expression (VEGFR2ce) in relation to survival in metastatic breast cancer (MBC) patients (pts) treated with bevacizumab (Bev).
Authors: Borba Roseana Melo , Felismino Tiago Cordeiro , Da Costa Alexandre Andre B. A. , Lima Vladmir C. , Corassa Marcelo , Bezerra Stephania , Osorio Cynthia Bueno de Toledo , Paiva Tadeu Ferreira
Published: September 2018

11523

Background: Bev is a monoclonal antibody that binds to VEGFA that demonstrated improved progression free survival (PFS) in MBC clinical trials. VEGFR2, NOTCH1, Integrin a1b2 and ILK are angiogenesis-related proteins possibly related with Bev efficacy. The correlation of these proteins expression and Bev survival variables was evaluated. Methods: We retrospectively analyzed 1st line chemotherapy in two HER2 negative MBC cohorts. Pts were treated between May-07 and July-14. Cohort 1 (C1) was treated with paclitaxel and Cohort 2 (C2) with paclitaxel and Bev. Expression of biomarkers was determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. Survival curves were calculated by Kaplan-Meier method and log-rank test. Cox model was used in multivariate analysis. Results: C1 had 42 pts. Median age was 63y. Tumor subtypes were divided in luminal (92.9%) and triple negative (TN) (7.1%). Visceral metastasis (mets) were present in 71.4%. Median follow-up (mFUP) time was 32.1m. mPFS was 8.0m and mOS was 33.5m. C2 had 29 pts. Median age was 57y. Luminal 79.3%; TN 20.7%; Visceral mets 79.3%; mFUP 38m. mPFS was 10.5m and mOS was 47m. In C2, high VEGFR2ce was correlated with improved PFS (high VEGFR2 16.5m x low VEGFR2 6.8m, p = 0.025). Breast cancer subtype, metastasis pattern and VEGFR2 expression were included in the multivariate analysis for PFS. VEGFR2 remained as independent factor (HR 0.35; IC95% 0.14 – 0.85, p = 0.021). In C1, VEGFR2 was not correlated with improved PFS (high VEGFR2 8.6m x low VEGFR2 8.0m, p = 0.24). Other markers were not associated with PFS. Conclusions: High VEGFR2ce was associated with increased PFS in patients treated with Bev. In MBC VEGFR2 may have a role as a predictive tool on benefit of antiangiogenic therapy.
Circulating tumor cell status and benefit of radiotherapy in stage I breast cancer.
Authors: Goodman Chelain Rae , Seagle Brandon-Luke L , Donnelly Eric Donald , Strauss Jonathan Blake , Shahabi Shohreh
Published: September 2018

11524

Background: Circulating tumor cell (CTC) status has been shown to be prognostic of decreased survival in non-metastatic breast cancer. While up to 20-30% of patients with early breast cancer have detectable CTCs, less is known regarding the role of CTC-status in guiding clinical management. Methods: An observational cohort study was performed on women with stage I breast cancer evaluated for CTCs from the 2004-2014 National Cancer Database. Logistic regression was used to explore clinicopathological associations with CTC-status. Kaplan-Meier and multivariable Cox proportional-hazards survival analyses were used to estimate associations of CTC-status with overall survival using a propensity score-adjusted and inverse probability-weighted matched cohort. Results: Of the stage I breast cancer women evaluated for CTCs, 23.1% (325/1,407) were CTC-positive. Age, histology, receptor status, and nodal stage were associated with CTC-status. CTC-status was an effect modifier of the radiotherapy-survival association: CTC-positive women who did not receive radiotherapy had an increased hazard of death compared to CTC-negative women who also did not receive radiotherapy (four-year survival: 85.7% vs. 93.3%, HR = 2.92, CI = 1.43-5.98, P = 0.003). CTC-positive patients treated with radiotherapy did not have decreased survival compared to CTC-negative patients not treated with radiotherapy (HR = 0.67, CI = 0.28-1.65, P = 0.40). From the matched cohort analysis, CTC-positive women who did not receive radiation had a 4.82-fold increased hazard of death compared to CTC-positive women treated with radiotherapy (four-year survival: 83.2% vs. 96.6%; CI = 2.62-8.85, P < 0.001). Conclusions: Treatment with adjuvant radiotherapy was associated with improved survival in CTC-positive women with stage I breast cancer. If prospectively validated, CTC-status may be valuable as a predictor of benefit of radiotherapy in early stage breast cancer.
Association of circulating tumor DNA clearance during treatment with improved progression-free survival in advanced non-small cell lung cancer patients.
Authors: Lu Shun , Song Yong , Xie Zhanhong , Li Min , Zhu Zhengfei , LIU LI , Dong Xiaorong , Chen Yuan , Zheng Di , Zhao Weixin , Chang Jian Hua , Jin Meiling , Hu Jie , Tong Gangling , Rao Chuangzhou , Xu Haiyan , Zhang Lu , Mao Xinru , Han-Zhang Han , Liu Hao
Published: September 2018

11528

Background: Currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, which do not reflect biological processes at the molecular level. We utilized circulating tumor DNA (ctDNA) coupled with capture-based ultra deep next generation sequencing to conduct dynamic monitoring of treatment response, thus evaluating the ability of ctDNA as a tumor clonal response biomarker. Methods: We performed capture-based sequencing on longitudinal plasma samples, including baseline and a minimum of 2 evaluation points, obtained from 88 patients with advanced NSCLC using a ctDNA panel, spanning 160KB of human genome and consisting of critical exons and introns from 168 genes. This real world study comprises a highly heterogeneous cohort with a mixture of prior treatment exposure. Results: At baseline, treatment-naïve patients often harbor solo driver mutation; in contrast, patients with prior treatments are more likely to harbor concurrent driver mutations. Patients who received molecular targeted therapy according to the baseline sequencing results have a longer progression-free survival (PFS) (p = 0.0001), demonstrating the value of ctDNA in directing treatment. During subsequent evaluations, we observed 74% concordance rate between molecular and radiographic responses. Furthermore, our data revealed that during follow-up, patients with at least one time of undetectable ctDNA are associated with a longer PFS (p = 5.52e-6), regardless the type of treatment commenced. Among 44 patients who had at least one time of undetectable ctDNA, 39 achieved partial response or stable disease as their best response. Collectively, this phenomenon reflects clonal response, thus demonstrating the biological nature underlying the clinical response assessed by imaging modalities. Conclusions: This real world study demonstrates that patients with at least one time of ctDNA clearance during subsequent evaluation are associated with a longer PFS. Our study warrants further investigations to explore the value of ctDNA clearance as a surrogate endpoint of efficacy and as a risk stratification factor.
Prevalence and heterogeneity of androgen receptor splice variants and intra-AR structural variation in patient with castration-resistant prostate cancer.
Authors: Dirix Luc Yves , De Laere Bram , van Dam Pieter-Jan , Whitington Tom , Mayrhofer Markus , Henao Diaz Emanuela , Van den Eynden Gert , Vandebroek Jean , Del-Favero Jurgen , Van Laere Steven J , Gronberg Henrik , Lindberg Johan
Published: September 2018

11530

Background: Androgen receptor splice variant 7 (AR-V7) is linked to a priori resistance to abiraterone acetate and enzalutamide. However, AR-V7 negativity does not necessarily indicate responsiveness and up to 20% of AR-V7 positive patients do demonstrate moderate response to these second-line endocrine therapies. Methods: Peripheral blood samples from patients with CRPC (n = 30) starting a new line of systemic therapy were subjected to comprehensive profiling of AR. AR splice variant (ARV) profiling for eight isoforms was performed by targeted RNA-Seq on CellSearch-enriched circulating tumour cells. Low-pass whole-genome and targeted sequencing of the entire AR gene in plasma-derived circulating cell-free DNA allowed the assessment of copy number status and structural rearrangements, respectively. ARV expression, structural variation, copy number alterations and ligand-binding domain mutations were combined and correlated to clinicopathologic parameters. Results: Twenty-five out of 30 patients (83%) demonstrated an aberration in AR. Twenty out of 30 patients (66.7%) demonstrated AR amplifications. Interestingly, 15/30 patients had intra-AR structural variants, of whom 14 expressed ARVs. In the context of endocrine treatment, 15/26 (57.7%) patients were ARV-positive with 13/15 patients having less than 6 months benefit from their therapy (Fisher’s exact test, p = 0.0115). ARV expression was heterogeneous with 10/15 ARV-positive patients expressing several ARV. Notably, AR-V7 was most frequently detected, however AR-V3 was 3.5x more abundant (Wilcox signed rank, p = 0.0029). In 17 patients, a baseline AR profile was available and demonstrated how having any ARV was associated with progression-free survival (HR: 4.53, 95%CI: 1.424–14.41; p = 0.0105). In the poor response group, 6/17 (35.2%) were AR-V7 negative, of whom 4 carried other AR aberrations. Conclusions: Comprehensive AR profiling on liquid biopsies is feasible and provides new insights into the mechanisms driving endocrine resistance. Clinical validation, by means of a non-interventional, prospective and multicentric study, is essential and currently ongoing.
Prognostic impact of PD-1, PD-L1, and CD8 genes expression in peripheral blood in gastric cancer.
Authors: Ito Shuhei , Masuda Takaaki , Fukagawa Takeo , Kouyama Yuta , Wakiyama Hiroaki , Yoshikawa Yukihiro , Noda Miwa , Kidogami Shinya , Hu Qingjiang , Sato Kuniaki , Nambara Sho , Saito Tomoko , Sakimura Shotaro , Hayashi Naoki , Kuroda Yousuke , Eguchi Hidetoshi , Sasako Mitsuru , Mimori Koshi
Published: September 2018

11531

Background: Programmed death 1 (PD-1)/PD-1 ligand (PD-L1) blocking agents to gastric cancer (GC) in the clinical setting show significant therapeutic promise. However, since these agents are enormously expensive and potentially toxic, it is crucial to identify predictive biomarkers for detecting the best candidate who would benefit from these agents by less invasive and simpler method, such as liquid biopsy. Methods: Expression levels of genes coding for PD-1, PD-L1 and CD8 (CD8+ T cells are closely associated with cellular immune responses to tumors) were assessed in peripheral blood (PB) samples using quantitative RT-PCR. Samples were obtained from 407 GC patients (392 patients with neoadjuvant chemotherapy [NAC] and 15 patients without NAC) before surgery and 23 PB from normal controls (NC). Flow cytometric analysis was performed to identify PD-1-expressed cells in PB mononuclear cells. Results: PD-1, PD-L1 and CD8 mRNA levels of GC patients were significantly higher than those of NC: 4.2-, 3.0- and 6.1-fold increases, respectively (P < 0.0001, P = 0.0001 and P < 0.0001). PD-1 mRNA levels were significantly lower in GC patients with NAC than in GC patients without NAC (P < 0.01). GC patients with low PD-1, high PD-L1 and low CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, low PD-L1 and high CD8 mRNA levels, respectively (P < 0.05, P < 0.05 and P < 0.05). Multivariate analysis showed that PD-1 low/ PD-L1 high mRNA levels was independent risk factors for OS (OR 2.15, 95%CI 1.29-3.45, P < 0.01). Flow cytometric analysis demonstrated the proportion of CD3 (T cell marker)-positive cells in the PD-1-positive fraction were 95.4 ± 6.9% in GC patients. Thus, most PD-1 protein expression occurred on T cells. Taken together, PD-1, PD-L1 and CD8 mRNAs in PB were overexpressed in GC patients, and PD-1 mRNA levels which was mostly expressed on T cells in protein levels in PB were decreased in GC patients with NAC. Furthermore, relative levels of PD-1, PD-L1 and CD8 were associated with prognosis, respectively. Conclusions: Preoperative PD-1, PD-L1 and CD8 mRNA levels in PB may reflect antitumor immune response, and PD-1 low/ PD-L1 high mRNA levels in PB are markers of poor prognosis in GC patients.
Evaluation of liquid biopsies for molecular profiling in patients with advanced non-small cell lung cancer (NSCLC) in the relapse treatment setting.
Authors: Remon Jordi , Besse Benjamin , Lacroix Ludovic , Mezquita Laura , Jovelet Cecile , Howarth Karen , Plagnol Vincent , Morris Clive D. , Nicotra Claudio , Pannet Chloe , Green Emma , Soria Jean-Charles
Published: September 2018

11532

Background: Molecular profiling is limited by access to sufficient tumor tissue for comprehensive analysis and due to tumor heterogeneity, the complete range of tumor DNA abnormalities may not be represented nor accurately reflect the clinical evolution of disease. Circulating tumor DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for the detection, quantification and monitoring of molecular abnormalities for personalized treatment strategies. Methods: In a prospectively designed program, to date, we have recruited 227 advanced NSCLC patients having received prior therapy, with unknown molecular profile at time of blood collection. Blood collections (10ml K2-EDTA) were performed to assess molecular profile prior to or at time of relapse. Repeat samples were performed on patients initiated on treatment and followed for up to 18months. Patient samples were analyzed with InVision (enhanced tagged-amplicon sequencing) using a 34 gene panel. Interim analysis performed with full descriptive summary statistical analyses to be presented at conference. Results: ctDNA profiling detected somatic mutations in 182pts (80.2%), predominantly located in TP53 (46%), EGFR (28%), KRAS (11%) and STK11 (7%, half of which had concurrent KRAS). Of note, clinically actionable mutations were detected: T790M (25pts, median 1.4% AF), ERBB2 (8 pts), MET (8pts) and BRAF (4pts) providing eligibility for new therapy options. 20pts including 12 EGFR/T790M+ve were evaluated for ctDNA monitoring up to 18 months (median 10m); correlation between dynamic change in mutation allele fraction and clinical response was observed, especially predictive of relapse to treatment. 10 patients demonstrated SD/PR response to osimertinib treatment with T790M detection at low allele fraction (7/10 < 1% AF with 1pt at 0.08% AF). Conclusions: ctDNA can be used as a non-invasive ‘liquid biopsy’ for molecular profiling of NSCLC patients to detect clinically relevant and actionable mutations when tissue biopsy is unavailable. Liquid biopsies can be repeated as needed where tissue is not feasible, providing real-time information to support personalised treatment.
CK19 combined with contrast-enhanced ultrasound: A prediction model for non-sentinel lymph node involvement in early breast cancer.
Authors: Yu Xingfei , Zhou Linyan , Liang Chenlu , Wang Chen , Li Yongfeng , Yu Yang , Chen Daobao , Yang Chen , Yang Hongjian , Huang Jian
Published: September 2018

11539

Background: According to Z0011 and AMAROS trials, patients with breast cancer stage cT1~2cN0 and sentinel lymphnode (SLN) 1~2 involvement can avoid axillary lymphnode dissection (ALND). But the risk of non-sentinel lymphnode (nSLN) involvement in those early stage patients is still unclear and it is difficult to predicting the risk before surgery. Our previous study showed CK19 mRNA in peripheral blood had predicative value of nSLN involvement. Also, contrast-enhanced ultrasound (CEUS) is a new effective method exmaming axillary lymph node. We aim to establish a prediction model for nSLN involvement in early breast cancer using CK19 combined with CEUS score. Methods: We identified 119 cases diagnosed early breast cancer (stage cT1~2cN0 and 1~2 SLNs involvement as in Z0011 and AMAROS trials) from Oct 2015 to Nov 2016 in Zhejiang Cancer Hospital. The CK19 mRNA of peripheral blood by RT-PCR and CEUS score of axillary lymph nodes were acquired before surgery. We used logistic regression analysis for filtering out valuable predictive clinical parameters and establishing formulas to calculate the probability of nSLN involvement. Our model was compared with Memorial Sloan Kettering Cancer Center (MSKCC) nomogram, which is one of the most reliable and validated methods for predicting of nSLN. Results: The histological grade, CK19 and CEUS score were screened by logistic regression analysis into the formula to calculate the probability of nSLN involvement. The sensitivity, specificity, total accuracy of this model was 89.13%, 80.82% and 84.03%, respectively. The false negative rate was 10.87%. The model had high quality of consistency (Kappa 0.675, p < 0.01) and goodness of fit (likelihood-ratio test, -2log liklihood = 84.607). The area under curve (AUC) of ROC was significantly higher (P < 0.01) in our model (0.914, 95%CI, 0.863~0.965) than in MSKCC nomogram (0.563, 95%CI, 0.459~0.667). Conclusions: The prediction model based on CK19 and CEUS score has satisfying sensitivity, specificity and accuracy, more effective than MSKCC nomogram. It is a valuable model of evaluating the risk of nSLN involvement in early breast cancer before surgery, picking out the patients who can truly avoid ALND.
Early TKI-pharmokinetics and circulating tumor DNA (ctDNA) to predict outcome in patients with EGFR-mutated non-small cell lung cancer (NSCLC).
Authors: Bigot Frederic , Pecuchet Nicolas , Blanchet Benoit , Laurent-Puig Pierre , Blons Helene , Goldwasser Francois , Boudou-Rouquette Pascaline , Auclin Edouard , Oudard Stephane , Fabre Elizabeth
Published: September 2018

11544

Background: Erlotinib (E) and gefitinib (G) are indicated as first-line therapy of EGFR-mutated NSCLC patients (pts). Many studies highlighted TKI pharmacokinetic (PK) impact on toxicities. However, data about the relationship between PK and efficacy are sparse. Recently, ctDNA has been shown to be a strong prognostic factor for metastatic NSCLC pts undergoing specific treatment. Thus, we underwent an observational study to determine plasma drug concentration and ctDNA impact on outcomes in NSCLC pts treated with E or G. Then, we explored the correlation between PK and ctDNA in order to improve management of pts treated with EGFR-TKI. Methods: We analyzed consecutive pts with EGFR-mutated NSCLC treated with TKI in Cochin and European Georges Pompidou hospitals (APHP, Paris) from April 2010 to March 2016. Plasma samples were collected 2 to 6 weeks after TKI initiation. Steady state trough concentration (Cssmin) was assessed by high performance chromatography. CtDNA was analyzed using Next-Generation Sequencing (Ampliseq ColonLungV2 panel, BPER method). Therapeutic ranges obtained from previous studies were between 1200 to 2000 ng/mL and > 200 ng/mL for E and G, respectively. Results: Out of 77 pts, 56 had Cssmin analysis, 40 ctDNA analysis and 31 both. Median age was 70 years (range: 31-90), 49 were treated with E, 24 with G. Median follow-up was 19 months. Whatever EGFR TKI, pts with Cssmin into therapeutic ranges had longer PFS than pts over or under-exposed (median: 17.5 vs 7.5 months, p = 0.002). Those with early indetectable ctDNA had significantly better PFS (median 13 vs 5.8 months, p = 0.01) and OS (median: 21.4 vs 14.3 months, p = 0.02). No correlation was found between ctDNA and Cssmin. Occurrence of toxicity > grade 2 in pts treated with E was associated with higher plasma concentration (mean 1991 vs 1184 ng/mL, p < 0.01). Conclusions: Early Cssmin and ctDNA assessment appear as markers to predict outcomes. Our observational study is the proof of concept that pts undergoing EGFR-TKI therapy could be monitored with Cssmin and ctDNA to define optimal personalized treatment strategies. A prospective study is planned to evaluate dose adaptation of TKI based on those 2 tools.
Exosomal Del-1 as a potent diagnostic marker for breast cancer: A prospective cohort study.
Authors: Lee Soo Jung , Lee Jeeyeon , Jung Jin Hyang , Park Ho Yong , Lee Chan-Hyeong , Moon Pyong-Gon , Baek Moon-Chang , Jeong Jae-Hwan , Park Ji-young , Chae Yee Soo
Published: September 2018

11548

Background: The authors recently reported exosomal Del-1 as a diagnostic marker for breast cancer (Moon PG et al, Clin Cancer Res. 2016). Therefore, the current study aimed to confirm the diagnostic role of exosomal Del-1 in a prospective cohort with breast cancer by comparing plasma exosomal Del-1 levels before and after curative surgery. Methods: To identify the optimal time of sampling after surgery, blood samples were serially collected at day 1, 3, 5, and 7 after surgery from 22 patients with breast cancer. Thereafter, one hundred fourteen breast cancer patients who underwent curative surgery were prospectively enrolled and then their exosomal Del-1 levels before and after surgery were compared using ELISA with both anti-Del-1 and anti-CD63 antibodies. Results: Among 22 patients for identifying the optimal sampling time, all the exosomal Del-1 levels were normalized at post-operative day (POD) 1 (0.5 or less), and therefore POD 3 or later was accepted for the sampling time for 114 prospective patient cohort.At diagnosis, exosomal Del-1 levels of 110 (96.5%) patients were higher ( > 0.5) and 109 (99.1%) patients showed a normalization of Del-1 after surgery including four patients with the borderline Del-1 (between 0.4 and 0.5). During the mean follow-up duration of 21.8 (range, 5.9 – 58.4) months, nine (7.9%) patients experienced relapses (4 loco-regional and 5 distant), where 3 out of 6 in high group ( > 0.5), 2 out of 4 in borderline group, and 4 out of 105 in normalized group (≤0.4). In particular, patients who relapsed in higher Del-1 group showed earlier relapse compared to the relapsed patients in lower Del-1 group. Conclusions: As the current prospective cohort study demonstrated a normalization of exosomal Del-1 after curative surgery, exosomal Del-1 can be confirmed as a potent diagnostic biomarker for breast cancer. Plus, a high Del-1 level after surgery seems related with early relapse suggesting a potential prognostic marker by identifying the existence of residual tumor.
Prognostic value of NK and T-lymphocytes markers in operable non-small cell lung cancer (NSCLC).
Authors: Skrzypski Marcin Tomasz , Szymanowska-Narloch Amelia , Jassem Ewa , Marczyk Michał , Polanska Joanna , Biernat Wojciech , Rzyman Witold , Maciejewska Agnieszka , Pawlowski Ryszard , Jassem Jacek
Published: September 2018

11556

Background: Therapies aimed at activation of T and NK cells are developed to expand NSCLC treatments options. It is conceivable that markers of ‘immune ignorant’, ‘immune excluding’ or ‘inflamed’ tumor phenotypes could be prognostic or predictive of benefit from specific immune-targeting therapies. Aim: To assess the prognostic value of expression of T and NK cells mRNA markers and immune-related genes in early stage NSCLC. Methods: qRT-PCR was used to assess 48 mRNAs levels in frozen cancer tissue sections and matched normal lung parenchyma from 56 surgically treated stage I-IIIA NSCLC patients. The mRNA expression (normalized vs. 4 reference genes) was compared between the groups that did (44%) or did not relapse, as well as clinicopathological features (33% never-smokers, 75% lung adenocarcinoma). Results: Low expression of FAS-L (p.adj. = 0.048) , TIGIT and LAG3 was correlated with shorter distant metastasis free survival (DMFS) (p < 0.04). Expression of PD-1 (p = 0.024) and CTLA4 (p = 0.04) was significantly lower in relapsed vs. non-relapsed NSCLCs, whereas there was no difference for PDL-1 and PDL-2. Expression of NK activation markers: NCR3 and NCR1, but not NCR3-ligand 1 was significantly lower in relapsed vs. not relapsed NSCLCs. Other NK cell markers: CD96 and NKG2D were expressed at lower levels (p = 0.02) in relapsed vs. not relapsed NSCLCs, whereas there was no difference for NKG2C and NKG2A. Expression of CXCR3 was lower in relapsed NSCLCs (p = 0.03), however, the expression of its ligands (chemoattractants for lymphocytes) - CXCL9, CXCL10 or CXCL11 or endothelin receptor type B was not different according to metastatic status. GITR and FOXP3 expression was significantly higher in cancers vs. normal lung parenchyma (p.adj. < 0.003). There were no differences in expression according to gender, smoking or NSCLC histological types. Conclusions: Non-inflamed NSCLC phenotype is associated with higher risk of dissemination after primary resection. Neoplastic tissue is characterized by higher level of immune tolerance in comparison to normal lung tissue.