bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive molecular profiling of high-risk relapsed neuroblastoma by plasma cell-free DNA analysis.
Authors: Kothari Prachi , Yang Julie , Berger Michael F. , Shukla Neerav Narendra , Modak Shakeel , Tsui Dana
Published: September 2018

10552

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. 5-year survival rates for high-risk NB are < 50% despite intense multimodality treatment. Recent studies revealed that as opposed to diagnostic samples, relapsed NB tumors have a significantly higher mutational burden as a result of clonal evolution. This poses a challenge for the development of personalized therapies and warrants molecular profiling at relapse. However, tumor samples are not always accessible at relapse. Our study evaluates the feasibility of using cell-free DNA (cfDNA) to noninvasively characterize tumor profiles at relapse to identify targetable genetic variants. Methods: Tumor specimens, plasma and matched control samples from 10 patients with high-risk stage 4 NB were collected during multimodality treatment. Samples were analyzed using the MSK-IMPACT platform, a targeted deep sequencing assay to interrogate the exons and selected introns of 410 actionable genes. Tumor samples were collected from surgeries performed either at diagnosis, disease progression, or relapse. Plasma samples were collected at a time of disease progression, at an average 395 days (range of 47-1597 days) from tumor collection. Matched control samples were used to filter germline variants. Results: We detected somatic mutations and copy number alterations in tumor tissues and cfDNA of 10/10 and 6/10 patients, respectively. These included recurrent NB drivers such as MYCN amplification and ATRX mutations. In 4 patients, cfDNA also revealed somatic variants that were not detected in the original tumor specimens, including potentially targetable mutations in NRAS, MLL2, CIC and IDH2 that were recently reported to be enriched in the relapse setting, as well as ARID1B mutation that is associated with poor prognosis. Conclusions: This study suggests that it is feasible to noninvasively profile the dynamic genetic heterogeneity of NB by plasma cfDNA analysis. Such analysis can potentially supplement tumor profiling especially in the relapse setting to guide treatment plans. Our findings call for incorporation of cfDNA analysis in clinical trials to further evaluate its utility for clinical management of NB patients.
Solid organ transplant after treatment for childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Dietz Andrew Charles , Seidel Kristy , Leisenring Wendy M. , Mulrooney Daniel A. , Tersak Jean M. , Glick Richard D. , Burnweit Cathy A , Green Daniel M. , Diller Lisa , Oeffinger Kevin C. , Smith Susan A , Howell Rebecca M. , Stovall Marilyn , Robison Leslie L. , Armstrong Gregory T. , Termuhlen Amanda M.
Published: September 2018

10559

Background: Childhood cancer therapy is associated with late onset, organ-specific impairment. However, the prevalence of and outcomes after solid organ transplant (SOT) in childhood cancer survivors (CCS) are unknown. Methods: Data on U.S-based participants in the Childhood Cancer Survivor Study were linked with the Organ Procurement and Transplantation Network. Cumulative incidence of transplant (CIT) 35 years after cancer diagnosis, multivariable Cox regression models for hazard ratios (HR), Kaplan-Meier (KM) survival and corresponding 95% confidence intervals (CI) were estimated. Results: Among 13,318 survivors, median follow-up age 39 years (interquartile range, IQR 33-46), and median time since cancer diagnosis 31 years (IQR 28-36 years), 100 CCS had SOT after study entry with characteristics and outcomes provided (table). Conclusions: Organ-specific radiation and chemotherapy exposure increase the risk for SOT after childhood cancer. Five-year survival rates after renal and cardiac SOT are favorable. [Table: see text]
Experience of implementing a novel random sampling BICR audit for investigator (INV)-assessed progression-free survival (PFS) in the PALOMA-3 trial.
Authors: Huang Xin , Zhang Ke , Turner Nicholas C. , Bartlett Cynthia Huang , Giorgetti Carla , Cristofanilli Massimo
Published: September 2018

1058

Background: PFS has frequently been used as a primary endpoint for evaluating efficacy of anticancer therapies in randomized clinical trials. Given high correlation between INV and independent (BICR) assessments with respect to the relative treatment effect, a pre-planned BICR audit of INV progression assessment in a random subgroup of patients (pts) instead of a BICR review of all progression assessments can be an acceptable approach to verify the INV assessments and to evaluate the potential bias in INV PFS results. Methods: PALOMA-3 was a randomized, double blind, placebo (PCB) controlled, Ph 3 study with the primary objective of demonstrating the superiority of palbociclib (PAL) + fulvestrant (F) over PCB + F in women with HR+, HER2- metastatic breast cancer (MBC). The primary endpoint was INV assessed PFS. BICR assessment of PFS was performed with the use of a novel audit approach involving a random sample–based BICR to verify if the INV assessed PFS was accurate. A third-party core imaging laboratory performed the blinded review for a randomly selected subgroup of pts (~40%). NIH and PhRMA methods were used to evaluate the potential for bias in the INV PFS results. Results: PAL + F improved PFS in patients with HR+, HER2- MBC. The observed INV HR was 0.46 (95% CI: 0.36, 0.59; stratified 1-sided p < 0.0001) in favor of PAL + F. The median PFS was 9.5 mo (95% CI: 9.2, 11.0) in the PAL + F arm and 4.6 mo (95% CI: 3.5, 5.6) in the PCB + F arm (Lancet Oncol. 2016; 17: 425–39). The estimated HR of the complete BICR data incorporating the information from the complete INV assessed PFS and the random sample audited BICR subgroup was 0.33 with the upper bound of the 1-sided 95% CI of 0.47. The results confirmed the INV assessed treatment effect and detected no INV bias in favor of PAL + F. Conclusions: PALOMA-3 is the first registrational trial to use a BICR audit and has received positive reviews from regulatory agencies. The experience of implementing the random sampling BICR audit in PALOMA-3 demonstrates that this approach can be used for randomized, double blind oncology trials with solid tumors where INV assessed PFS is the primary endpoint and a large treatment effect is targeted. Sponsor: Pfizer. Clinical trial information: NCT01942135.
RADICAL trial: A phase Ib/IIa study to assess the safety and efficacy of AZD4547 in combination with either anastrozole or letrozole in ER positive breast cancer patients progressing on these aromatase inhibitors (AIs).
Authors: Seckl Michael , Badman Philip David , Liu Xinxue , MacPherson Iain R. , Zubairi Ishtiaq Husain , Baird Richard D. , Garcia-Corbacho Javier , Cresti Nicola , Plummer Elizabeth R. , Armstrong Anne Caroline , Allerton Rozenn , Landers Donal , Nicholas Hanna , McLellan Lyndall , Lim Adrian K. , Coombes Charles
Published: September 2018

1059

Background: Patients with metastatic ER positive breast cancer invariably experience disease progression whilst taking AIs. Fibroblast growth factor receptor inhibitors (FGFRI) such as AZD4547 can reverse endocrine resistance in breast cancer cells. Consequently, we designed the RADICAL trial to test the safety and efficacy of AZD4547 combined with letrozole (L) or anastrozole (A). Methods: Patients with prior disease progression on either AI were initially recruited to a Phase Ib study which showed that L 2.5mg or A 1mg daily continuously could be safely combined with AZD4547 80mg twice daily on a 1wk on/1 wk off schedule. Pharmacokinetic data showed no significant interactions. Subsequently, 52 patients progressing on these AIs were recruited, either continuing, or, if other therapies had subsequently been given, restarting their prior AI together with AZD4547. Primary endpoint was change in tumour size (RECIST v 1.1) at 12 weeks compared to baseline. Results: Enrolled patients had previously received a median of 4 (range: 1-11) systemic therapies, including endocrine treatments with a median of 2 (range: 1-6). The mean tumour size change at 12 and 28 weeks was 7% (95%CI: -4%, 17%) and 8% (95%CI: -4%, 20%), respectively. Clinical benefit assessed by partial response (PR) or stable disease (SD) occurred in 36.5% (1 PR and 18 SD) and 25% (2 PR and 11 SD) of patients at 12 and 28 weeks, respectively. The median progression free survival was 3.1 months (95%CI: 2.4-5.4). Most adverse events (AEs) were G1/2 (95.3%). 11 (21%) patients developed asymptomatic AZD4547-induced retinal pigment epithelial detachment, all resolved and 1 and 6 were able to continue on study medication at full and half dose, respectively. Among 34 G3/4 AEs, only 6 were probably/possibly related to AZD4547. Out of 13 unrelated serious AEs, 2 were fatal. Conclusions: Combined AZD4547 with L or A appears to be safe and shows anti-tumour activity in advanced ER+ patients resistant to these AIs. Development of a biomarker to select patients for this therapy will facilitate future studies. Clinical trial information: NCT01791985.
Analysis of everolimus starting dose as prognostic marker in HR+ mBC patients treated with everolimus (EVE) + exemestane (EXE): Results of the 3rd interim analysis of the non-interventional trial BRAWO.
Authors: Fasching Peter A. , Grischke Eva-Maria , Schuetz Florian , Decker Thomas , Uleer Christoph , Salat Christoph , Foerster Frank , Schmidt Marcus , Mundhenke Christoph , Tesch Hans , Jackisch Christian , Wimberger Pauline , Aktas Bahriye , Zahn Mark-Oliver , Tome Oliver , Bloch Wilhelm , Hanson Sven , Fischer Thomas , Schubert Joerg , Lueftner Diana
Published: September 2018

1061

Background: BRAWO is a German non-interventional study, which enrolled more than 2400 patients (pts) with advanced/metastatic, hormone-receptor-positive and HER2-negative breast cancer treated with EVE and EXE. Main objectives are a) the impact of physical activity on efficacy and quality of life, b) prophylaxis and management of stomatitis in clinical routine, and c) the sequence of therapy when EVE is used in daily clinical practice. Methods: In this update on the results of the 3rd interim analysis (data cut-off 18-Oct-2016) we analyzed under real world conditions the first 1.078 patients followed up until disease progression for their progression-free survival (PFS) events. A two-stage process based on a Cox regression model was used to check the relevance of the start dose on PFS. In the first step potentially relevant covariates defined by medical experts were evaluated for relevance. In the second step start dose and all covariates showing a p-value of at most 0.1 in first step including all two-interaction of start dose with these parameters were included into the model. Results: Our multivariate analysis support the evidence that predictive factors, such as body mass index (BMI, p-value: < 0.001), therapeutic line (1st vs. 2nd+3rd vs. ≥4th; p-value: 0.013), presence of visceral metastases (p-value: < 0.001) and ECOG (Eastern Cooperative Oncology Group, p-value: < 0.001) status at the beginning of the therapy correlated significantly with the PFS. 283 patients started with 5mg and 795 Patients started with 10 mg. Starting dose had no significant impact on the PFS (neither as main effect nor within interactions, p-value: 0.44-0.88). Conclusions: Even though the approved and recommended starting dose for treatment with EVE is 10 mg, physicians sometimes start EVE-treatment with a lower starting dose, trying subsequently to increase the dose to the recommended dose of 10mg to allow the patient’s organism to adapt to the therapeutic. As the study was not powered to detect possible differences in PFS by starting dose, the result of showing no detrimental effect of a lower start dose may be the result of limited power. Clinical trial information: EUPAS9462.
Fulvestrant as maintenance therapy after first-line chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer (FANCY), a prospective, multicenter, single arm phase 2 study.
Authors: Wang Shusen , Zheng Qiufan , Xu Fei , Xia Wen , Ouyang Quchang , Pang Danmei , Yuan Huimin , Shi Yanxia , Peng Roujun , Yuan Zhongyu
Published: September 2018

1066

Background: Fulvestrant is potent for treatment of hormone receptor (HR)-positive advanced breast cancer (ABC); however, few data exist for this regimen as maintenance endocrine treatment after chemotherapy (CT). In our phase 2 trial, we aimed to assess efficacy and tolerability of fulvestrant 500mg as maintenance therapy in patients with disease control after first-line CT. Methods: Simon’s two-stage design was used. We enrolled postmenopausal women with histologically confirmed HR-positive, HER2-negative ABC, who achieved disease control after four to eight cycles of first-line CT. Fulvestrant 500 mg was intramuscularly injected on day 1, 15, 29, then every 28 (±3) days subsequently, until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR), secondary endpoint included progression-free survival (PFS) since maintenance treatment, PFS since first-line CT, objective response rate (ORR) and safety. Results: Between Dec 10, 2013, and Sept 30, 2015, 58 patients were enrolled. 25 (43%) patients were deemed as resistance to endocrine treatment, 36 (62%) patients had a visceral disease. Median follow-up was 21 months. After fulvestrant maintenance treatment, 36 patients remained disease stabilising for at least six months, and eight (14%, 95% CI 6-25) patients achieved a response, resulted in a CBR of 76% (95% CI 63-86), which met its primary endpoint. The median PFS since fulvestrant treatment was 16·1 months (95% CI 10·3 to not reached), and median PFS since first-line CT was 19·5 months (95% CI, 15·6 to not reached). 39 (67%) of 58 patients reported at least one adverse event (AE), of which predominantly were grade 1 or 2. The most common grade 3 AEs were increased alanine aminotransferase in two (3%) patients, increased aspartate aminotransferase in one (2%) patient, and arthralgia in one (2%) patient. No patient discontinued treatment due to AE. Conclusions: Fulvestrant 500mg is active in maintenance therapy in non-progrssion patients with HR-positive ABC after first-line CT. Further study is needed to assess long-term outcome of maintenance therapy. Clinical trial information: NCT02000193.
Evolution of overall survival according to year of diagnosis (2008-2014) and subtypes, among 16703 metastatic breast cancer (MBC) patients included in the real-life "ESME" cohort.
Authors: Delaloge Suzette , Ezzalfani Monia , Dieras Veronique , Bachelot Thomas Denis , Debled Marc , Jacot William , Brain Etienne , Mouret-Reynier Marie-Ange , Goncalves Anthony , Dalenc Florence , Patsouris Anne , Ferrero Jean-Marc , Levy Christelle , Vanlemmens Laurence , Lefeuvre Claudia , Mathoulin-Pélissier Simone , Petit Thierry , Courtinard Coralie , Cailliot Christian , Pérol David
Published: September 2018

1078

Background: Real-life data may help checking that public investments match closely medical needs. During the last decade, several drugs have been released on the market for MBC on the basis of a potential impact on overall survival (OS). Based on the large real-life ESME cohort, we aimed to describe the time evolution of MBC OS according to main phenotypes. Methods: ESME is a unique MBC national cohort including all consecutive patients (pts) who initiated treatment for MBC between 1/01/08 and 31/12/14 in the 18 French comprehensive cancer centres. ESME collects retrospective data using clinical trial-like methodology including quality assessments. Database lock was 8/12/2016. Primary objective was the impact of year of MBC diagnosis on OS. Multivariate Cox regressions were used with adjustment for main prognostic covariates. Results: 15170 out of 16703 pts in ESME had full IHC data allowing their classification as HR+HER2- (N=9922), HER2+ (N=2863), or HR-HER2- (N=2321) cases. Median FU and OS for the whole cohort are 4.05 yrs [95 CI: 3.98-4.12], and 3.1 yrs [95 CI: 3.03-3.18] respectively. In the adjusted multivariate analysis, year of MBC diagnosis, age at MBC, subtype (using HER2+ as reference), disease-free interval (DFI), visceral involvement, and number (nbr) of metastatic sites are significant OS predictors (table) although with low effect for the first item. Age at MBC, DFI, visceral involvement, and nbr of metastatic sites remained significant prognostic variables in subtypes. Year of diagnosis was no longer significant in HR+HER2- nor HR-HER2- cases (HR=0.997, p=0.71 and HR=0.997, p=0.84), while it was highly significant in HER2+ cases (HR=0.91, p<0.0001). Conclusions: Although OS of MBC has slightly improved over the past decade, this remains mostly confined to HER2+ cases, highlighting the need for new strategies for the luminal and triple negative populations. [Table: see text]
A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results.
Authors: Attia Steven , Bolejack Vanessa , Ganjoo Kristen N. , George Suzanne , Agulnik Mark , Rushing Daniel A. , Loggers Elizabeth Trice , Livingston Michael B. , Wright Jennifer A. , Chawla Sant P. , Okuno Scott H. , Reinke Denise K. , Riedel Richard F. , Davis Lara Emily , Ryan Christopher W. , Maki Robert G.
Published: September 2018

11005

Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.
Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study.
Authors: Raut Chandrajit P. , Espat N. Joseph , Maki Robert G. , Araujo Dejka M. , Williams Toni Faith , Wolff Johannes E. , DeMatteo Ronald P.
Published: September 2018

11009

Background: Adjuvant IM reduces risk of recurrence and improves survival in pts with high-risk primary GIST. Joensuu et al 2016 demonstrated higher 5-yr overall survival (OS) rates of 91.9% vs 85.3% in pts treated with adjuvant IM for 3 vs 1 yr, respectively. It is unknown if further extension of treatment duration can improve outcome. Methods: PERSIST-5 is a single-arm, phase II trial that enrolled pts ≥18 yrs of age, who underwent macroscopically complete resection of primary KIT (+) GIST with high risk of recurrence within 12 wks prior to IM treatment. High risk was defined as primary GIST (any site) ≥2 cm with a mitotic count ≥ 5/50 HPF or non-gastric primary GIST ≥5 cm. Pts were treated with IM 400 mg/d for 5 yrs or until progression, relapse, or intolerance. Primary endpoint was recurrence-free survival (RFS, defined as time of treatment start to first recurrence or death). Results: IM was administered to 91 pts with a median age of 60 yrs (range 30-90). Median tumor size was 6.5 cm (range 2.3-30 cm; 55% gastric origin). Median treatment duration was 55.7 mos (range, 0.5-75). Forty-six (50.5%) pts completed study treatment. The 5- and 8-yr estimated RFS rates were 90% (95% CI, 80-95) and 81% (95% CI, 62-91), respectively. The 5- and 8 year OS rate was 95% (95% CI, 86-99). There were 7 recurrences; 1 pt recurred and died while on IM ( PDGFRA D842V mutation) and 6 pts recurred after IM discontinuation. Two pts died after IM discontinuation, unrelated to study treatment and without recurrence. Forty-five pts discontinued study treatment; common reasons included patient choice (20%), adverse events (AEs, 17%), protocol deviation (4%), and loss of follow-up (4%). The most common AEs of all grades (regardless of relationship to IM) were nausea (71%), diarrhea (63%), fatigue (50%), muscle spasm (41%), vomiting (39%), and periorbital edema (34%). Conclusions: Five yrs of IM treatment was effective in preventing recurrence in pts with sensitive mutations who underwent resection of primary GIST. Nearly half of the patients discontinued treatment early, and most recurrences occurred after IM discontinuation. Clinical trial information: NCT00867113.
Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST).
Authors: Heinrich Michael C. , Jones Robin Lewis , von Mehren Margaret , Schoffski Patrick , Bauer Sebastian , Mir Olivier , Cassier Philippe Alexandre , Eskens Ferry , Shi Hongliang , Alvarez-Diez Terri , Schmidt-Kittler Oleg , Healy Mary Ellen , Wolf Beni B. , George Suzanne
Published: September 2018

11011

Background: Oncogenic mutations in KIT or PDGFRα drive > 85% of GIST. However, primary and acquired mutations in the activation loop of PDGFRα and KIT are not effectively treated by approved therapies. A phase 1 study (NCT02508532) was initiated in advanced GIST to assess the safety, PK and clinical activity of BLU-285, a potent, highly-selective oral inhibitor that targets KIT Exon 17 and PDGFRα D842 activation loop mutants. Methods: Adult patients (pts) with unresectable GIST, who had received ≥2 kinase inhibitors including imatinib or who had a primary PDGFRα D842 mutation regardless of prior therapy, were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design, which allowed additional accrual to dose levels demonstrated to be safe. Adverse events (AEs) per CTCAE v4.03, PK and plasma/tumor mutant DNA levels were assessed. Response was determined by RECIST 1.1 every 8 weeks. Results: At a 01JAN17 cutoff, 40 pts (21 PDGFRa/19 KIT) have been treated with BLU-285 at doses of 30-600 mg. Median number of prior kinase inhibitor regimens was 4.5 (2-12) KIT/2.5 (0-4) PDGFRα. RECIST 1.1 responses were seen across all dose levels for PDGFRα GIST and at higher dose levels for KIT GIST. Of 17 PDGFRα D842V pts with ≥1 radiographic assessment, 7 had confirmed PR (ORR 41%) and 10 had SD. Of 11 evaluable KIT pts treated at doses ≥ 135 mg, 2 had PR (1 confirmed; ORR 18%) and 5 SD. BLU-285 is rapidly absorbed (Tmax 2-8 h), exposure increases linearly with dose, and half-life is > 24 h supporting QD dosing. Most AEs were grade 1 or 2, most commonly nausea (48%), fatigue (45%), peripheral edema, periorbital edema, vomiting (30% each), diarrhea (25%), anemia, dizziness, and lacrimation (23% each). There were no grade 4 or 5 BLU-285-related AEs, dose limiting toxicities, or discontinuations. 29 pts (all 21 PDGFRα pts) remain on treatment (duration 1-14 mo). Updated results including MTD, ct-DNA and central radiographic assessments will be presented. Conclusions: Precision targeted therapy with BLU-285 demonstrates important clinical activity in pts with both PDGFRα- and KIT-mutant GIST that is resistant to available therapies. Clinical trial information: NCT02508532.
Phase (Ph) 2 stage 1 clinical activity of seviteronel, a selective CYP17-lyase and androgen receptor (AR) inhibitor, in women with advanced AR+ triple-negative breast cancer (TNBC) or estrogen receptor (ER)+ BC: CLARITY-01.
Authors: Gucalp Ayca , Danso Michael A. , Elias Anthony D. , Bardia Aditya , Ali Haythem Y. , Potter David , Gabrail Nashat Y. , Haley Barbara B. , Khong Hung T. , Riley Elizabeth Carloss , Ervin Leigh , Eisner Joel Robert , Baskin-Bey, M.D. Edwina , Moore William Richard , Traina Tiffany A.
Published: September 2018

1102

Background: Seviteronel (Sevi), an oral selective CYP17-lyase and AR inhibitor that blocks testosterone and estradiol production and competitively antagonizes the AR, is in Ph 2 clinical development for BC and prostate cancer. The primary objective of this ongoing Ph 2 study (NCT02580448) is to estimate the activity of once daily Sevi in women with AR+ TNBC and ER+ BC as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wk), respectively. Methods: Patients (pts) with ER+/HER2-normal metastatic BC following progression of ≥1 prior line of endocrine therapy or TNBC were enrolled with no limit of prior therapies in either cohort. Evaluable pts had AR ≥10% via central IHC staining (TNBC only) and 1 post-baseline scan. Sevi was administered at 450 mg oral daily. Scans were performed every 8 wk. Circulating tumor cell (CTC) enumeration was performed by EPIC CTC analysis. A Simon’s 2-stage design was employed to determine activity (≥2 of 13 CBR16 in TNBC and ≥2 of 12 CBR24 in ER+ BC allow for accrual to Stage 2). Results: As of 4 Oct, 2016, 16 pts with AR+ TNBC (6 evaluable) and 14 pts with ER+ BC (11 evaluable) were enrolled. 67% had visceral metastases; 10% had stable brain metastases. 60% had ≥2 lines of prior therapy for advanced disease. 13 of 14 (93%) TNBC pts who underwent central AR testing had AR ≥10%. Four pts in the TNBC cohort and 8 pts in the ER+ cohort remain on therapy. CBR16 (TNBC) and CBR24 (ER+) was 2 of 6 (33%) and 2 of 11 (18%) allowing Stage 2 accrual in both cohorts. 7 of 10 evaluable pts with CTCs present at baseline had a CTC decline at C2D1, including all that met CBR (-94.3% [-27.5, -100] median [range]). The most common adverse events (≥ 25%) were fatigue (50%), nausea (43%) and decreased appetite (33%); all Grade 1/2. Updated CBR data will be presented at the time of presentation. Conclusions: Sevi Stage 1 activity is suggested by CBRs, along with associated CTC declines in heavily pre-treated pts with high disease burden. The observed safety profile is consistent with on-target pharmacology. Stage 2 enrollment is ongoing. Sevi may provide a novel treatment option for women with AR+ TNBC or ER+ BC. Clinical trial information: NCT02580448.
Osteosarcoma prognostic nomograms for predicting the 10-year probability of mortality and recurrence.
Authors: Wang Haotong , Miao Ruoyu , Jacobson Alex , Goldberg Saveli , Harmon David C. , Cote Gregory , Hornicek Francis J , Raskin Kevin , Nielsen Gunnlaugur , DeLaney Thomas F. , Choy Edward , Chen Yen-Lin
Published: September 2018

11020

Background: The multidisciplinary approach in treatment of osteosarcoma has been well established and well adopted nationwide. This study combined the clinical prognostic factors at initial presentation into a nomogram to predict local control (LC), metastasis free survival (MFS), and overall survival (OS) for patients with non-metastatic bone osteosarcoma. Methods: We reviewed 397 osteosarcoma patients treated from 1995 to 2014. Patients with metastatic disease at diagnosis or limited follow up were excluded, resulting in 283 cases for analysis. Clinical and pathologic variables were recorded. Predictive variables included age at diagnosis, gender, previous radiation history, site, tumor size, histologic subtype, histologic grade, extra-osseous extension (EOE), lymphovascular invasion (LVI), necrosis rate and margin. The multivariate Cox proportional hazards regression was used to analyze survival outcomes and risk variables. Results: At 10 years, LC was 70.4% (95% confidence interval, CI: 64.0%-76.7%), MFS was 64.7% (95% CI: 58.1%-71.3%), and OS was 61.5% (95% CI: 54.9%-68.1%). Multivariate Cox model identified age (p = 0.033), site (p = 0.020), EOE (p = 0.017), LVI (p = 0.011), and margin (p = 0.039) were correlated with LC; age (p = 0.028), tumor size (p < 0.001), histologic grade (p = 0.039), and LVI (p = 0.014) were correlated with MFS; whereas age (p < 0.001), prior radiation history (p = 0.010), tumor size (p = 0.002), histologic subtype (p = 0.012), EOE (p = 0.002), and LVI (p = 0.001) were associated with OS. The nomograms were drawn on the basis of the Cox regression model and were internally validated using bootstrapping, with predictive accuracy of ±7.2% for 10-year LC, ±7.4% for 10-year MFS, and ±7.5% for 10-year OS. Conclusions: Nomograms have been developed to predict the 10-year local-control failure, recurrence and death. We suggest that this tool at presentation may be useful for individualized risk evaluation, patient counseling, and making clinical decisions.
Inhibition of autophagy sensitizes gastrointestinal stromal tumor cells to TKI/Bcl-2 inhibitors-induced apoptosis.
Authors: Zhang Shuchao , HU Guozhi , Paz-Mejia Ana Cristina , Li Luyuan , Trent Jonathan C.
Published: September 2018

11036

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the GI tract. Most GISTs are driven by mutations in KIT or platelet-derived growth factor receptor-α (PDGFRA), which responds well to imatinib, a tyrosine kinase inhibitor (TKI) that blocks KIT and PDGFR-α signaling. Bcl-2 family plays a critical role in the regulation of cell apoptosis in GISTs. ABT-737 as an inhibitor of Bcl-2/Bcl-xL can result in a time and dose-dependent activation of apoptosis. Autophagy is a key mechanism to promote tumor cells survival, inhibition of which can induce the cell death in GISTs. Chloroquine, an antimalarial drug, has been also identified as an autophagy inhibitor. In this study, we assessed the combinational effects of imatinib, ABT-737 and chloroquine in GIST cells. Methods: Human GIST cell lines, GIST-T1 and GIST-882, were employed in our study. Cells were treated with imatinib, ABT-737 and chloroquine either separately or in different combinations. Cell viability was tested by means of MTS and synergistic effects were analyzed by isobologram software. The levels of related proteins of apoptosis (PARP, Caspase-3) and autophagy (LC3-II, beclin-1) were measured by western blot. Cell apoptosis and cell cycle were tested by flow cytometry. Results: Cell viability assay indicated cell survival percentage of double or triple drug combinations ( < 5%) dramatically decreased compared to single drug treatments (42%, 36% or 12%) ( P< 0.05). Isobologram analysis revealed triple drugs combination had stronger synergistic effects than double drugs combinations (CI = 0.204 vs 0.309 or 0.356, P< 0.05). Cell apoptosis percentage of double (32.9% or 36.6%) or triple drugs combinations (66.5%) significantly increased compared to single treatments (6.1%, 6.1% or 13.1%) ( P< 0.05). Western blot showed drugs combinations increased cleavage of PARP and Caspase-3 levels, but inhibited autophagy. Conclusions: The combination of imatinib, ABT-737 and chloroquine has collaborative effects on the treatment of GISTs in vitro. The combined strategy may enhance the clinical efficacy, which provides a rationale for the clinical evaluation of these drug combinations in GISTs treatment.
Influence of chemotherapy combined with radiotherapy on the time-to-development of radiation-induced sarcomas: A multicenter, retrospective analysis.
Authors: Zhang Alison Yan , Judson Ian Robert , Benson Charlotte , Wunder Jay , Ray-Coquard Isabelle Laure , Grimer Robert , Quek Richard Hong Hui , Wong Eva , Miah Aisha , Ferguson Peter Charles , Dufresne Armelle , Teh Jonathan Yi Hui , Stockler Martin R. , Tattersall Martin HN
Published: September 2018

11046

Background: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present an international multi-centre collaborative study to validate this association. Methods: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between the 1st January, 2000 to 31st December, 2014. The primary endpoint was time to development of RIS, defined as the date of diagnosis of the first malignancy to date of the RIS diagnosis. We also assessed the relationship between chemotherapy, patient and cancer characteristics, and time to RIS. Results: We identified 419 patients with RIS, who were predominantly diagnosed with their first malignancy at adulthood. The median interval from the index cancer to development of RIS for the entire cohort was 11 years (range 1-64). Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1·37; 95% CI: 1·08-1·72; P = 0·009). In the multi-variable model, older age (HR 2·11; CI 1·83-2·43; P < 0·001) and chemotherapy for the first malignancy (HR 1·61; CI 1·26-2·05; P < 0·001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect. Conclusions: This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of a RIS. Our data highlights the importance of vigilance in surveillance for RIS after chemotherapy and radiation therapy, particularly in younger patients who also have a longer potential time to develop a second malignancy.
Trabectedin and radiotherapy in soft-tissue sarcoma (TRASTS) study: An international, prospective, phase I/II trial—A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) groups study.
Authors: Gronchi Alessandro , Hindi Nadia , Cruz Josefina , Blay Jean-Yves , Sanfilippo Roberta , Morosi Carlo , Romero Jesus , Peinado Javier , Lopez-Pousa Antonio , Alvarez Alvarez Rosa Maria , Italiano Antoine , Perez Jose Luis , Sangalli Claudia , Sunyach Marie Pierre , Romagosa Cleofe , Ranchère-Vince Dominique , Collini Paola , Martin Broto Javier
Published: September 2018

11061

Background: Myxoid liposarcoma/round cell liposarcoma (ML) exhibits especial sensitivity to trabectedin (T). In prospective series, long-lasting T treatment showed responses in 44% of patients (pts) with ML. ML is also sensitive to radiation therapy (RT) and preclinical data suggested radiosensitizing properties of T. Preoperative short-course of T with concurrent low-dose RT was conducted in a multicenter, European, phase I/II trial. We present here data from the phase I part in pts with centralized diagnosis of locally advanced, resectable ML. Methods: Pts received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8Gy/fraction). The phase I had the classic 3+3 design. Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2). Dose-limiting toxicity (DLT) were defined as grade ≥3 events excluding G3/4 neutropenia lasting < 5 days and G3-4 nausea/vomiting due to inadequate prophylaxis. RECIST responses were evaluated preoperatively at week 10. Surgical specimens were processed for histologic changes and residual tumor. Results: From February 2015 to May 2016,14 pts (M/F 7/7) with median age 36y (24-71) and median tumor size 12.5 cm were enrolled. 7 pts received T at dose Level 1 and 7 pts at Level 2. One DLT (G3 transaminitis) occurred at Level 1 and another (sepsis due to catheter infection) at Level 2. Overall, grade G 3/4 AEs were: ALT elevation (n = 6, 43%), and GGT elevation, neutropenia, anemia, epithelitis and sepsis (n = 1, 7% each). There were no deaths. One pt developed metastasis after C3 and did not undergo surgery; another one had a sepsis after C1 and received definitive RT. All pts completed RT. 13 pts were evaluable for response: 5 achieved PR (38%), 7 SD (53%), 1 distant PD (8%). 12 pts underwent surgery (7 R0/5 R1). Median viable residual tumor was 5% (0-60) with 9/12 pts (75%) with ≤ 10% viable remaining tumor, 3/12 (25%) complete responses. Conclusions: T in combination with RT was feasible and well tolerated in the preoperative setting. T dose of 1.5 mg/m2 is the recommended phase II dose. A high proportion of patients achieved a good pathological response, with 3/12 (25%) complete responses. Clinical trial information: 2014-001549-26.
Rhabdomyosarcoma (RMS) in adults: Histologic subtypes and overall survival with actinomycin-based chemotherapy vs doxorubicin-based chemotherapy.
Authors: Vang Alia , Robinson Steven Ian , Okuno Scott H.
Published: September 2018

11073

Background: RMS typically occurs in children. Vincristine, Actinomycin and Cyclophosphamide (VAC) based chemotherapy is the current standard. Limited data exist on the frequency of the histologic subtypes and optimal chemotherapy regimen for the treatment of adult patients with RMS. Methods: We retrospectively identified patients ≥18 years with RMS seen at our institution from 2000-2015. The analysis was performed with JMP statistical software. Results: We identified 73 patients, with a median age of 51 (range 18-85 years). The majority of patients were male (40 of 73) and presented with localized disease (59 of 73). Histologic subtypes were as follows: 32% embryonal (E), 27% alveolar (A), 36% pleomorphic (P), and 6% variants (V) (botryoid and spindle cell/sclerosing). The median overall survival (OS) for patients with localized disease was 16.2 months and metastatic disease 9 months. The median OS for patients with localized disease treated with VAC was 20.3 months (4A, 7E, 3P) and VDC (vincristine doxorubicin cyclophosphamide) was 14.1 months (3A, 3E, 2P). For those with localized disease treated with a VAC/actinomycin-based chemotherapy had a median OS of 19.5 months (4A, 9E, 3P) and with a VDC/doxorubicin-based chemotherapy had a median OS of 15.9 months (8A, 5E, 13P, 2V). Conclusions: Adult patients with RMS have an even distribution among the histologic subtypes. Given the small, unbalanced number of patients in each histologic subtype treated with VAC/actinomycin-based or VDC/Doxorubicin-based regimens, the overall survival benefit favoring the use of VAC/actinomycin-based is hypothesis generating and confirmatory studies are needed to truly determine the optional regimen for adult patients with RMS.
RAS mutations concordance in circulating tumor DNA (ctDNA) and tissue in metastatic colorectal cancer (mCRC): RASANC, an AGEO prospective multicenter study.
Authors: Bachet Jean-Baptiste , Bouche Olivier , Taïeb Julien , Dubreuil Olivier , Garcia Marie-Line , Meurisse Aurelia , Gornet Jean-Marc , Artru Pascal , Louafi Samy , Soularue Emilie , Baumgaertner Isabelle , Coriat Romain , Tougeron David , Lecomte Thierry , Mary Florence , Marthey Lysiane , Blons Helene , Taly Valerie , Bonnetain Franck , Laurent-Puig Pierre
Published: September 2018

11509

Background: RAS mutational status is required to prescribe anti-EGFR antibodies in mCRC. In comparison to molecular testing from tumor tissue, the characterization of RAS mutations in ctDNA is a promising and credible way to shorten the workflow. This study reports for the first time the performance of plasma testing in a large prospective series. Methods: Blood samples were prospectively collected before 1st line chemotherapy in mCRC patients. ctDNA was centrally assessed by NGS using the colon lung cancer V2 Ampliseq panel and by methylation digital PCR assay (WIF or NPY). Tumor tissue testing was done according to routine practice in each center. We expect a minimal kappa coefficient of 0.7 to reflect concordance. In order to have a precision of ± 0.07 with an estimated 5% of non-exploitable data 425 pts had to be included. Results were analyzed separately in the whole study population and in the subgroup of pts with ctDNA evidenced either by the presence of at least 1 mutation or by the presence of 1 methylated biomarker. Results: From 07/2015 to 12/2016, 425 patients were included, and 406 plasma samples were available for analysis. A RAS mutation was detected in 183 plasma samples (45.1%) As compared to tumor mutational status the kappa coefficient was 0.68 (95%CI: 0.61-0.75) with a concordance of 83.7%. Primary tumor removal, metachronous status, absence of liver metastases and peritoneal carcinomatosis were significantly associated with mutant RAS tumor and negative plasma status. In the subgroup of 324 samples for which ctDNA was evidenced, kappa coefficient was 0.85 (95%CI: 0.80-0.91) with a concordance of 92.9%. 23 pts had discordant results: RAS mutation in tumor tissue and not in ctDNA (15 pts, 4.6%), RAS mutation detected in ctDNA but not in tumor tissue (8 pts, 2.5%). Rectal tumor, absence of liver metastases, peritoneal carcinomatosis and tumor tissue cellularity < 10% were associated with discordant cases. Conclusions: We confirm, in this large prospective multicenter study, the high concordance rate for RAS status assessment between blood and tumor samples. This result argues for the use of blood testing in daily practice for pts with detectable ctDNA. Clinical trial information: NCT02502656.
Changes in computer extracted features of vessel tortuosity on CT scans post-treatment in responders compared to non-responders for non-small cell lung cancer on immunotherapy.
Authors: Velcheti Vamsidhar , Alilou Mehdi , Khunger Monica , Thawani Rajat , Madabhushi Anant
Published: September 2018

11518

Background: Immune-checkpoint blockade treatments demonstrate promising clinical efficacy in patients with non-small cell lung cancer (NSCLC). Nivolumab is a PD-1 inhibitor that is FDA approved for treatment of patients with chemotherapy refractory advanced NSCLC. The current standard clinical approach to evaluating tumor response is sub-optimal in defining clinical benefit from immunotherapy drugs. We sought to evaluate whether computer extracted measurements of vessel tortuosity significantly and differentially change post treatment between NSCLC patients who do and do not respond to immunotherapy. Methods: A total of 50 NSCLC patients including pre- and post- treatment CT scans were included in this study. The patients were either responders or non-responders to Nivolumab. Patients who did not receive Nivolumab after 2 cycles due to lack of response or progression as per RECIST were classified as ‘non-responders’. A total of 35 tortuosity features of the vessels around the lung nodules were investigated. In the training cohort (N = 25), the features were ranked based on the degree of change between pre- and post- treatment CT. The top 4 features were used for training a Support Vector Machine (SVM) classifier to identify which patients did and did not respond to immunotherapy on a validation cohort of N = 25 patients. Results: The top features identified were the ones associated with the curvature of the vessel branches. The AUC for the SVM classifier was 0.75 for the training and 0.79 for the test set. Conclusions: Changes in specific vessel tortuosity features between baseline and post-treatment CT scans following nivolumab were different between NSCLC patients who did and did not respond. Multi-site validation of the vessel tortuosity features is needed to establish it as a predictive biomarker for NSCLC patients treated with immunotherapy.
Cell-free DNA (cfDNA) mutations from clonal hematopoiesis: Implications for interpretation of liquid biopsy tests.
Authors: Razavi Pedram , Li Bob T. , Hou Chenlu , Shen Ronglai , Venn Oliver , Lim Raymond S. , Hubbell Earl , De Bruijn Ino , Liu Qinwen , Vijaya Satya Ravi , Xu Hui , Shen Ling , Sehnert Amy , Maddala Tara , Berger Michael F. , Aravanis Alex , Reis-Filho Jorge S. , Lee Mark , Solit David B. , Baselga Jose
Published: September 2018

11526

Background: A large fraction of cfDNA fragments are derived from hematopoietic sources. Somatic alterations in cfDNA can be tumor-derived but also could represent somatic changes associated with clonal hematopoiesis. We performed deep sequencing of both plasma cfDNA and matched white blood cell (WBC) genomic DNA (gDNA) to determine the contribution of clonal hematopoiesis to the variants observed in cfDNA. Four cohorts were investigated: metastatic breast (BC), non-small cell lung (NSCLC), castration-resistant prostate cancer (CRPC), and non-cancer participants (pts). Methods: Metastatic cancer pts with de novo or progressive disease were prospectively enrolled. Non-cancer pts were blood bank donors. Plasma cfDNA and matched WBC gDNA were sequenced using a targeted 508-gene panel (2 Mb) to > 60,000X raw depth. Variant calling used a novel pipeline that employed molecular barcoding for error suppression followed by de novo assembly and graph-based variant calling. Results: Of 151 metastatic cancer pts (48 BC, 49 NSCLC, 54 CRPC), median age was 64 (30-87) with 53% female and 33% treatment naive. Of 47 non-cancer pts, median age was 61 (20-78) with 51% female. Analysis of cfDNA identified 1072 variants (AF > 0.1%, > 2 mutant reads, passing bioinformatic quality filters) which were also detected in WBC gDNA as non-germline ( < 35% allele frequency [AF]) non-synonymous variants. For these cfDNA variants, AF ranged from 0.1-14.4% and correlated with AF in WBC gDNA (r2 = 0.47, p < 0.001). Mutated genes were consistent with clonal hematopoiesis, with the most frequently mutated genes being DNMT3A, TET2, PPM1D, and TP53 (215, 77, 45, and 36 variants, respectively). For both cancer and non-cancer pts (age > 45), median number of overlapping variants was 5 per pt (range 0-22). The number of WBC gDNA and cfDNA variants per individual was positively associated with age (p < 0.001) in both cancer and non-cancer pts (interaction p = 0.08). Conclusions: Somatic cfDNA variants are frequently derived from clonal hematopoiesis and increase with age. Accurate assessment of somatic alterations in cfDNA should account for this phenomenon to distinguish between tumor-derived and WBC-derived variants.