bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary side of origin affects the outcome of mCRC patients treated with first-line FOLFIRI plus bevacizumab independently of BRAF status and mucinous histology.
Authors: Loupakis Fotios , Yang Dongyun , Zhang Wu , Cremolini Chiara , Wakatsuki Takeru , Salvatore Lisa , Antoniotti Carlotta , Aprile Giuseppe , Schirripa Marta , Ricci Vincenzo , Lucchesi Sara , Masi Gianluca , Maus Martin Karl Herbert , Lonardi Sara , Ning Yan , El-Khoueiry Rita , Falcone Alfredo , Lenz Heinz-Josef
Published: March 2020

3549

Background: Several studies tried to address the question of whether primary site of CRC could affect the outcome. Those analyses were limited by small sample size numbers and/or high degree of heterogeneity in stage and received treatments and/or limited information regarding molecular and pathologic features. Mucinous histology and BRAF mutations are more frequent in right-sided tumors and are both associated with worse outcome in the metastic setting. Methods: the analysis was conducted on a database of 455 mCRC prospectively enrolled in a pharmacogenetic translational study. Patients (pts) were treated with FOLFIRI/bevacizumab. Pts were excluded if data regarding mucinous histology and/or BRAF mutational status were lacking or if affected by synchronous right and left-sided tumors. Results: 200 pts were identified and included in the study. Mucinous histology, BRAF mutation and right-side primary were found in 35 (17.5%), 14 (7%) and 56 (28%) patients respectively. Right-side tumors were more frequently BRAF mutated (p<0.001) and the association was still significant when adjusting for mucinous histology (p=0.001). There was a trend in the association between mucinous and side (p=0.082). At a multivariate analysis, pts with right-side primary were at higher risk of progression (HR=1.88 [95%CI: 1.25-2.84], p=0.0026) and death (HR=2.07 [95%CI: 1.23-3.49], p=0.006). At a prespecified analysis in the subgroup of non-mucinous and BRAF wild-type tumors, pts with right-side primary achieved median PFS and OS of 10.0 and 28.9 mos compared to 13.0 and 47.6 mos of left-side (PFS, right vs left: HR=1.87 [95%CI: 1.19-2.91], p=0.003; OS: HR=1.91 [95%CI: 1.07-3.39], p=0.022). This was again confirmed in a multivariate model. Conclusions: These data underline a possible strong impact of side on the outcome of mCRC treated with first-line FOLFIRI plus bevacizumab. To give a biological explanation for these results, a GWAS on germinal DNA and gene-expression analyses on tumors are ongoing. In order to clarify the prognostic vs predictive role to antiangiogenic treatments of this feature analyses from 2 phase III randomized trials have been planned.
Improved early prediction of individual prognosis for patients with mCRC: Joint modeling of tumor shrinkage with volume data for PFS and OS.
Authors: Mansmann Ulrich Robert , Laubender Ruediger Paul , Sartorius Ute , Giessen Clemens Albrecht , Graser Anno , Heinemann Volker
Published: March 2020

3603

Background: Piessevaux et al. (ESMO 2010) proposed a decrease in RECIST-based tumor size of 20% at week 8 following 1st-line therapy for mCRC as a predictor of clinical outcome (PFS and OS). We expanded upon this idea (ASCO GI 2012). A tumor volume algorithm was developed providing a better approximation to true tumor volume by using both the longest and the longest orthogonal diameters of a target lesion. In this study we compare the quality of early prediction-based individual patient prognosis based on tumor change according to either RECIST or the tumor volume algorithm. Methods: The prognostic method is combined with the volume algorithm and applied to the data from 2 studies (OPUS, n=337; CRYSTAL, n=1198) and 4 treatment regimens (FOLFOX4 +/- cetuximab and FOLFIRI +/- cetuximab), in patients with mCRC. The influence of the treatment regimen on early PFS and OS prognosis is studied by joint modeling. The quality of early prognosis depending on the tumor size assessment used is compared by the logarithmic scoring rule. Results: Individual volume shrinkage and baseline volume are considered prognostic factors. Individual predictions depend on the chemotherapy administered and whether cetuximab is added. Equivalent tumor baseline volumes and early volume changes, predict an up to 20% higher 1 year (y) PFS and 2y OS rate for FOLFIRI than for FOLFOX. The addition of cetuximab to standard chemotherapy (CT) translates into a mean increase in shrinkage of 10% resulting in an improvement in 1y PFS rates of 23% and in 2y OS rates of 18%. The quality of individual prediction over the 4 regimens is combined in one logarithmic (log) score. The log score for the RECIST-based prediction is 2.45 which is significantly higher than that for the volume-based prediction of 1.97 (p<0.0001). Lower scores correspond to a better prediction. Conclusions: The tumor volume algorithm enables a more precise prediction of individual patient PFS and OS than RECIST-based tumor assessments. Based on early tumor changes for CT, +/- cetuximab, it is possible to calculate quantitative information on a patient’s prognosis. The model has high potential to guide individual clinical decision making for mCRC patients.
Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or placebo (P+O) among patients with advanced neuroendocrine tumors (NET).
Authors: Yao James C. , Hainsworth John D. , Wolin Edward M. , Pavel Marianne E. , Baudin Eric , Gross David , Ruszniewski Philippe , Tomassetti Paola , Panneerselvam Ashok , Saletan Stephen , Klimovsky Judith
Published: March 2020

4014

Background: In this large phase III trial, median progression-free survival (PFS) improved by 5.1 mo with E+O compared to P+O in patients (pts) with NET associated with carcinoid syndrome. Baseline imbalances including WHO performance status (PS) and primary site favoring P+O confounded primary analysis. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are important biomarkers in NET. Analyses were performed to identify prognostic factors and adjust for baseline imbalances. Methods: Pts were randomized to E+O (n=216) or P+O (n=213). Potential prognostic factors including baseline CgA (≤2×ULN vs >2×ULN), baseline 5-HIAA (≤median vs >median at baseline), age (<65 vs ≥65), gender, race, WHO PS (0 vs 1, 2), primary site (lung vs other), prior somatostatin analog use (yes vs no), duration from diagnosis (<6 mo, 6-24 mo, 2-5 yr, >5 yr), and organs involved (liver, bone) were assessed in univariate analysis using the log rank test and stepwise regression using Cox proportional hazards model. Results: Median PFS (mo) was significantly longer for pts with nonelevated CgA (27 vs 11; p<.001) and nonelevated 5-HIAA (17 vs 11; p<.001). Analyses also indicated age (14 vs 12; p=.01), WHO PS (17 vs 11; p=.004), liver involvement (14 vs not reached; p=.02), bone metastases (8 vs 15; p<.001), and lung as primary site (11 vs 14; p=.06) as potentially prognostic. Multivariate analysis indicated that significant prognostic factors for PFS included baseline CgA (HR, 0.47; CI, 0.34-0.65; p<.001), WHO PS (HR, 0.69; CI, 0.52-0.90; p=.006), bone involvement (HR, 1.52; CI, 1.06-2.18; p=.02), and lung as primary site (HR, 1.55; CI, 1.01-2.36; p=.04). Adjusted for covariates, a 38% reduction in risk of progression was observed for E+O (HR, 0.62; 95% CI, 0.51-0.87; p=.003). Conclusions: In the phase III RADIANT-2 trial, baseline CgA levels, WHO PS, lung as primary site, and bone involvement were important prognostic factors. Exploratory analysis adjusted for these prognostic factors indicated significant benefit of everolimus therapy.
Phase I/II study of preoperative (pre-op) short course chemoradiation (CRT) with proton beam therapy (PBT) and capecitabine (cape) followed by early surgery for resectable pancreatic ductal adenocarcinoma (PDAC) of the head.
Authors: Hong Theodore S. , Ryan David P. , Borger Darrell R. , Blaszkowsky Lawrence Scott , Yeap Beow Yong , Deshpande Vikram , Wo Jennifer Yon-Li , Wadlow Raymond Couric , Kwak Eunice Lee , Allen Jill N. , Clark Jeffrey W. , Zhu Andrew X. , Ferrone Cristina , Mamon Harvey J. , Adams Judith A. , Winrich Barbara , Grillo Tarin , DeLaney Thomas F. , Fernandez-del Castillo Carlos
Published: March 2020

4021

Background: Standard adjuvant 6 week CRT may delay and reduce tolerability of adjuvant gemcitabine-based chemotherapy. We explore the safety and efficacy of a one-week course of pre-op CRT with PBT and cape followed by early pancreaticoduodenectomy (PD). Methods: Patients with radiographically resectable, biopsy-proven PDAC of the head were enrolled from May 2007-December 2010 on this prospective, NCI-sponsored clinical trial. Eligibility included no CT involvement of SMA or celiac artery; No metastatic disease. Dose level 1 consisted of PBT delivered 3 Gy x 10. Pts in subsequent dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M W F, wk 2 T Th), level 3 (wk 1 M T Th F, wk 2 M), level 4 (wk 1 M-F). PBT was targeted at pancreatic mass with elective nodal coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. Surgery was performed 1-6 wks after completion of cape. Patients were recommended to receive 6 mo of gemcitabine after surgery. Genotyping of 15 genes (including KRAS, PIK3CA, BRAF, NRAS, TP53, IDH1) was performed. Results: 50 pts were enrolled on study. 48 patients are eligible for this analysis. 3 pts were treated at each of dose levels 1-3. 6 pts were at dose level 4, which was selected as MTD. No DLTs were observed. 35 patients were treated in the phase II portion at the MTD. Gr 3 toxicity was noted in 2 pts (chest wall pain-1, colitis-1). 38 pts underwent PD. Reasons for no PD were: metastatic disease-9, unresectable tumor-1. Mean post-op length of stay was 7 days (range 5-47). 6/38 (16%) resected pts had positive margins. 28/38 (74%) had positive nodes. Median follow up is 21 months among the 19 patients still alive. 4/48 (8%) local failures in ALL patients. mOS and mPFS are 18 and 10 months respectively for ALL patients and 27 and 14 months for RESECTED patients. Of 28 patients with genotype data available, 22 (79%) had KRAS mutations. 10/22 KRAS mt and 4/6 KRAS wt pts are alive. Conclusions: Pre-op CRT with 1 wk of PBT and capecitabine followed by early surgery is well tolerated and associated with favorable local control. Complete genotype and DPC4 data will be presented at the meeting.
Ethnic gene profile of genes involved in angiogenesis to predict regional bevacizumab efficacy difference in gastric cancer.
Authors: Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Loupakis Fotios , Azuma Mizutomo , Gerger Armin , Graziano Francesco , Ning Yan , Labonte Melissa Janae , El-Khoueiry Rita , Bohanes Pierre Oliver , Benhaim Leonor , Páez David , Watanabe Masahiko , Koizumi Wasaburo , Lenz Heinz-Josef
Published: March 2020

4026

Background: AVAGAST showed regional bevacizumab (Bev) efficacy difference (RBED), namely, Asian (Asi) patients (pts) with gastric cancer (GC) had no benefit whereas European and Pan-American patients had more benefit from Bev. Recently, germline gene polymorphisms in angiogenesis have been recognized as predictive marker for Bev efficacy. Allele frequency (AF) in gene polymorphisms may vary depending on ethnicity. We tested the hypothesis whether angiogenic pathway gene polymorphisms may have different AF among Asi, Caucasian (Cau), and Hispanic (Hisp) in GC and this disparity may explain RBED. Methods: Three-hundred pts [Japanese (Jap), Cau, and Hisp, 100 from each race] with histopathologically confirmed GC were collected from Japan, USA, Austria, and Italy between 1991 and 2011. These pts were divided into 2 groups as training set (n=50) and validation set (n=50) in each race. Seven functional gene polymorphisms previously reported as predictive marker were selected. All samples were analyzed using PCR-based direct DNA- sequencing. Fisher's exact test was used to compare the distribution of AF among races. Results: Significant disparate distributions in favorable AF for Bev were shown among races in Table. Jap GC pts had significant lower AF of 5 predictive gene polymorphisms in training set, and among these 5, three predictive gene polymorphisms were also validated. Conclusions: Our preliminary results showed significant disparate AF distributions in predictive gene polymorphisms for Bev, and these disparities may explain RBED in AVAGAST. Further investigation is warranted to elucidate RBED. [Table: see text]
Efficacy and safety of bevacizumab combined with chemotherapy in the treatment of patients with metastatic well-differentiated duodeno-pancreatic endocrine tumors (BETTER study).
Authors: Ducreux Michel , Seitz Jean-François , Smith Denis , O'Toole Dermot , Lepère Céline , Bitoun Laurence , Mitry Emmanuel
Published: March 2020

4036

Background: Gastrointestinal neuroendocrine tumors (NET) overexpress vascular endothelial growth factor (VEGF), thus we hypothesized that Bevacizumab (Bv), a monoclonal antibody targeting VEGF in combination with chemotherapy may show an activity in duodeno-pancreatic NET. Methods: This multicenter, open-label, non-randomized, two- group phase II trial assessed in one group the efficacy and safety of Bv (7.5 mg/kg IV on day 1, every 3 weeks), combined with 5-FU/streptozotocin (stz): 5-FU 400 mg/m²/d; Stz 500 mg/m²/d IV, d1-5/ every 42 days, during a minimum of 6 months in patients (pts) with progressive, metastatic, well-differentiated duodeno-pancreatic NET (WHO 2000), not previously treated with chemotherapy, ECOG PS ≤2 and Ki 67 index < 15%. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate, safety and quality of life. Study duration was 24 months. Results: In the ITT population, 34 pts were enrolled, 22 (64.7%) were men, median age 55.3 years (37.0-77.6), 33 (97.1%) pts had ECOG-PS 0/1. Most metastases were in the liver 33 (97.1%) pts or lymph nodes 14 (41.2%) pts. Ki-67 proliferative index was 0-2% in 8 (25%) pts, 3-4% in 5 (15.6%), 5-9% in 6 (18.8%), 10-14% in 12 (37.5%) and 15% in 1(3.1%) pt. Median treatment duration was 14.0 months; median number of cycles was 10. At 24 months, median PFS was 23.7 months [95%CI: 14.5; not reached] based on 18 events. PFS rate at 18 months was 62%. Tumor control rate was 100% (n= 34) including partial response in 19 (55.9%) pts and stable disease in 15 (44.1%) pts. Survival rate at 24 months was 88%. Median OS was not reached, 5 patients died. CTC grade 3/4 Adverse Events (AEs) occurred in 23 (67.6%) of pts, mainly digestive 5 (14.7%) pts. G3/4 Bv targeted AEs were hypertension in 7 (20.6%) pts and thromboembolism in 4 (11.8%). Conclusions: Efficacy data in this phase II trial assessing a novel approach with Bv and 5-FU/stz in duodeno-pancreatic NET is encouraging and the toxicity profile is acceptable. Results suggest that Bv may have a place in the treatment of pancreatic NET and warrant further investigation in a phase III trial.
Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric cancer (AGC) enrolled in the phase III GRANITE-1 study.
Authors: Yeh Kun-Huei , Van Cutsem Eric , Ohtsu Atsushi , Shen Lin , Ajani Jaffer A. , Rizvi Syed , Sedova Michaela , Costantini Chiara , Smith Heind , Sahmoud Tarek , Bang Yung-Jue
Published: March 2020

4081

Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol 2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the oral mammalian target of rapamycin inhibitor EVE showed that incidences of stomatitis, rash, infections, and pneumonitis were greater in Asian pts; however, the number of Asian pts enrolled was small. GRANITE-1 provides an opportunity to evaluate EVE safety in a broader Asian population. Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts aged ≥18 y with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d + best supportive care (BSC) or placebo + BSC. Randomization was stratified by region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was continued until disease progression or unacceptable toxicity. Adverse events (AEs) were collected throughout the study and for 28 d after final dose of study drug and assessed according to the Common Terminology Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival. Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363 (55%) were enrolled in Asia and received EVE (n=243) or placebo (n=120). EVE did not significantly reduce the risk of death in the overall (HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs 35%). Among EVE-treated pts, rates of any-grade rash, infections, and pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs 2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and 0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt (from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The safety profile of EVE in Asian pts with AGC was similar to that observed in ROW pts with AGC and with EVE in other cancers. No new safety signals were identified. Pneumonitis was relatively uncommon in Asian and ROW pts.
Relief of bowel-related symptoms with telotristat etiprate in octreotide refractory carcinoid syndrome: Preliminary results of a double-blind, placebo-controlled multicenter study.
Authors: O'Dorisio Thomas M. , Phan Alexandria T. , Langdon Robert M. , Marek Billie J. , Ikhlaque Nadeem , Bergsland Emily K. , Freiman Joel , Law Linda , Banks Phillip Lee , Frazier Kenneth , Jackson Jessica , Zambrowicz Brian , Kulke Matthew
Published: March 2020

4085

Background: Diarrhea associated with carcinoid syndrome has been attributed to tumor production of serotonin. Telotristat etiprate, (LX1032, LX1606), is an oral inhibitor of peripheral serotonin synthesis. This study explored the safety, tolerability, and efficacy of telotristat etiprate in carcinoid patients with octreotide-refractory diarrhea. Methods: Carcinoid patients with ≥4 bowel movements (BMs)/day on octreotide were randomized 3:1 to receive telotristat etiprate or placebo as double-blind treatment. Patients enrolled in sequential, escalating dose cohorts of 150, 250, 350, or 500 mg tid, followed by a 500 mg tid expansion cohort. Patients were followed for toxicity, 24-hr urinary 5-HIAA (u5-HIAA), BM frequency, and self-reported bowel-related symptoms. Subjects were asked “In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain or discomfort?” Responses (yes or no) were analyzed as categorical variables. Results: 16 patients enrolled in the 4 escalating dose cohorts and 7 in the expansion cohort; 18 on telotristat etiprate and 5 on placebo. Median age: 62 yrs; mean 6.3 BMs/day (range, 4-10). AEs included primarily mild-moderate diarrhea, nausea, and abdominal discomfort. In treated subjects, adequate relief was reported as: Week 1 - 6/18 (33.3%), Week 2 - 5/16 (31.3%), Week 3 - 5/15 (33.3%), and Week 4 - 6/13 (46.0%). No placebo subjects reported improvement at any timepoint. Biochemical response (≥50%reduction in u5-HIAA) and BM response (≥30% reduction in daily BMs for 2 weeks) were associated with reporting of adequate relief. For evaluable telotristat etiprate-treated patients, 9/16 (56%) experienced a biochemical response and 5/18 (28%) experienced a clinical (BM) response; no placebo subjects achieved either biochemical or clinical response. Conclusions: Treatment with telotristat etiprate was associated with decreases in u5-HIAA and BM frequency, and with self-reported relief of bowel related symptoms. Treatment in an extension phase with open-label telotristat etiprate is ongoing.
A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC).
Authors: Chi Kim N. , Hotte Sebastien J. , Ellard Susan , Gingerich Joel Roger , Joshua Anthony Michael , Yu Evan Y. , Gleave Martin Edwin
Published: March 2020

4514

Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at 12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31% treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts with CRPC. Funded by a grant from the Terry Fox Research Institute.
18F-16β-fluoro-5α-dihydrotestosterone (FDHT) PET as a prognostic biomarker for survival in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Fox Josef J. , Jia Xiaoyu , Heller Glenn , Schöder Heiko , Humm John , Haupt Eric C. , Schneider Coursen , Scher Howard I. , Larson Steven M. , Morris Michael J.
Published: March 2020

4517

Background: At present there is no imaging biomarker for patients with mCRPC as the disease primarily metastasizes to bone, which is difficult to visualize and quantify using standard techniques. We have conducted clinical trials in which patients with progressive mCRPC are scanned using FDG-PET to examine glucose metabolism, and FDHT-PET. FDHT is a novel tracer and structural analog of dihydrotestosterone that binds to the androgen receptor (AR) to demonstrate AR overexpression, a key biologic feature of mCRPC. We previously reported an association between baseline FDG-PET and overall survival in mCRPC. We now present the prognostic utility of baseline FDHT-PET. Methods: We prospectively scanned mCRPC patients with FDG and FDHT-PET prior to a change in therapy as part of imaging clinical trials. PET results were represented as the hottest lesion (SUVmax), or average of the five hottest lesions (SUVmaxavg). Five lesions per patient were recorded. If less than 5 lesions were captured, a value of 1 was imputed for the remaining lesions. Clinical and lab parameters were collected. Univariate analysis was performed on PET, clinical and lab variables for association with overall survival (OS). Multivariate models of prognostic factors were constructed. Results: 170 mCRPC patients were imaged with FDG and 116 also had FDHT-PET at baseline. Median survival was 21.2 months (95%CI: 19.1-24.0). On univariate analysis, FDHTmax, FDHTmaxavg, FDGmaxavg, PSA, hemoglobin, alkaline phosphatase, and LDH were associated with OS. FDHTmax and FDHTmaxavg were significantly correlated with one another. In a multivariate model, FDHTmaxavg and LDH were prognostic of survival. In a separate model assessing FDG, FDGmaxavg and LDH were also prognostic. Conclusions: FDHT not only allows for a visual assessment of the AR axis in prostate cancer, but appears to associate with overall survival in mCRPC. Increased AR activity as measured by FDHT SUVmaxavg held greater prognostic value than PSA or Gleason score. FDHT is also being evaluated as a clinical response indicator and pharmacodynamic measure with AR directed therapies.
Defining the genetic basis of everolimus sensitivity in metastatic bladder cancer (MBC) by whole-genome sequencing (WGS).
Authors: Iyer Gopa , Milowsky Matthew I. , Al-Ahmadie Hikmat , Hanrahan Aphrothiti , Janakiraman Manickam , Heguy Adriana , Viale Agnes , Socci Nicholas D , Sander Chris , Bochner Bernard , Bajorin Dean F. , Berger Michael F , Taylor Barry S. , Solit David B.
Published: March 2020

4527

Background: MBC is rarely cured with standard chemotherapy and novel agents are clearly needed. A phase II trial of everolimus in MBC resulted in 1 near-complete response (CR), 1 partial response, and 3 minor responses. We used WGS and a Next Generation exon capture assay to identify the genetic aberrations underlying treatment response. Methods: In the near-CR case, tumor and peripheral blood DNA was subjected to WGS (Illumina) using 2x100 bp paired-end libraries for 40X haploid coverage. Raw sequence data was aligned to hg19 and somatic point mutation detection was performed. Tumor DNA from 13 additional patients on the trial was analyzed using an exon capture sequencing assay. Results: 184 exonic somatic mutations were identified in the everolimus complete responder by WGS, including a 2 bp frameshift truncation in TSC1 and a nonsense mutation in NF2. Sanger sequencing of an additional 96 high-grade bladder tumors found 5 (6.2%) tumors containing TSC1 alterations and no NF2 mutations. Of the 13 patients on the trial who underwent targeted exon sequencing, 3 (23%) possessed nonsense TSC1 mutations and 2 had minor treatment responses (17% and 24% tumor regression). 1 patient with a 7% tumor regression had a somatic missense TSC1 variant. 8 (89%) of 9 patients with tumor progression as best response were TSC1 wild-type. Patients with TSC1-mutant tumors remained on drug for longer duration (7.7 vs. 2 months, p=0.004, Wilcoxon rank sum test). Conclusions: Everolimus is an active agent in MBC in patients with TSC1 mutant tumors. The pattern of co-mutation in patients with TSC1 mutant tumors is complex and combination therapies will likely be required to achieve durable responses in most patients. Our results also highlight the potential utility of WGS in identifying novel predictors of response to targeted inhibitors.
Phase II trial of bevacizumab (BEV)/high-dose chemotherapy (HDC) for refractory germ-cell tumors (GCT).
Authors: Nieto Yago , Tannir Nizar M. , Tu Shi-Ming , Jones Roy B. , Zurita Amado J. , Aparicio Ana , Bassett Roland , Margolin Kim Allyson , Holmberg Leona , Champlin Richard E. , Pagliaro Lance C.
Published: March 2020

4533

Background: HDC is a curative therapy for relapsed GCT. However, multiple prior relapses, cisplatin refractoriness (relapse/progression (PD) within 4 weeks) or absolute refractoriness (no prior response), or very high tumor markers at relapse predict poor early event-free survival (EFS). The validated Beyer model (JCO 1996;14:2638) identifies groups with poor risk (5% EFS at 1-year post-HDC), intermediate risk (25% EFS) or good risk (≥50% EFS). Given high VEGF expression in metastatic GCT and synergy between BEV and chemotherapy, we studied concurrent BEV/HDC in refractory GCT. Methods: Eligibility includes ≥ 1st relapse/PD, poor/interm risk and no contraindications to HDC or BEV. Treatment consisted of 2 cycles of HDC with stem-cell support following BEV (5 mg/kg) 1 week before each cycle. HDC-1 consists of a novel regimen of infusional gemcitabine with docetaxel/melphalan/carboplatin (BBMT 2005;11:297). HDC-2 includes ifosfamide/carboplatin/etoposide. Target accrual is 25 pts, to distinguish a 1-yr expected EFS of 15% (median time to progression [TTP], 9 months) from 50% 1-year EFS (median TTP, 2 years). Results: 21 pts have been treated, median age 22 (range, 19-45) poor risk (N=15) or interm risk (N=6), cisplatin refractoriness (N=9) or absolute refr (N=12), median 3 prior relapses (1-4), median 3 prior regimens (2-6), PD at HDC: 11 pts. Tumor sites: lungs (N=15), liver (8), bones (5), brain (5), retroperit (15), mediast (12). Histol at Dx: embryonal ca (4), chorio (3), mixed with teratoma (14). Prior surgery for metastases: 8 pts (6 abdomen, 1 liver, 1 brain). Prior radiation: 6 pts. Toxicity of HDC-1: grade 3 mucositis in all pts, rash (8 G2, 2 G3) and transaminase elevation; 2 pts with marginal baseline renal function died from early sepsis; 1 pt died from late fungal pneumonia. After HDC-1, markers normalized in 14/17 evaluable pts. 15 pts received HDC-2 at a median 49 (38-66) days after 1st stem cell infusion, which was well tolerated. 8 pts had residual lesions resected with findings of either teratoma (N=2) or no viable tumor (N=6). With median follow-up of 23 (3-43) months, 14 pts are alive in CR (67% EFS). Conclusions: BEV with HDCx2 shows encouraging preliminary results in heavily pretreated refractory GCT.
A pre-cystectomy decision model to predict pathologic upstaging and oncologic outcomes in clinical stage T2 bladder cancer.
Authors: Daneshmand Siamak , Skinner Eila C , Miranda Gus , Mitra Anirban Pradip
Published: March 2020

4578

Background: Neoadjuvant chemotherapy is the standard for advanced bladder cancer (BC), although its benefit in lower risk clinically organ-confined muscle-invasive (cT2N0M0) BC is uncertain. This study aimed to define pre-cystectomy factors in cT2N0M0 BC that could predict pathological upstaging at cystectomy and oncological outcomes. Methods: 1,964 institutional BC patients were reviewed. Neoadjuvant chemotherapy-naïve cT2N0M0 patients who underwent cystectomy were included. A multivariate classification and regression decision tree was used to assess hierarchical interactions of univariately significant variables, thereby identifying patients at greatest risk for upstaging and poor outcome. Results: 948 cT2N0M0 patients were identified; 512 (54%) were upstaged at cystectomy. Pathological upstaging was associated with poor RFS and overall survival (OS) (both p < 0.001). Age, lymphovascular invasion (both P = 0.01), multifocality (p = 0.004), deep muscle invasion, tumor growth pattern and hydronephrosis (all p < 0.001) were associated with upstaging. When these factors were included in a multivariate decision tree model, 71% of patients with hydronephrosis were upstaged and had the worst outcome (p < 0.001). In patients without hydronephrosis, tumor growth pattern was a second-tier discriminator; only 37% of patients with papillary tumors were upstaged. In patients with non-papillary tumors, deep muscle invasion was a third-tier discriminator; 70% of patients with invasion were upstaged. Age was a third-tier discriminator in patients with papillary + non-papillary features; 33% of patients ≤65 years were upstaged compared to 47% of patients >65 years. The decision tree was cross-validated and resulted in 3 risk groups – 5 year RFS/OS for low risk patients was 66%/48% versus 46%/27% for high risk patients (p < 0.001). Conclusions: This study identified pre-cystectomy variables that predict upstaging and poor outcomes in cT2N0M0 BC. The decision tree approach highlighted the most crucial prognostic variables, and can aid in identifying low risk patients in a stepwise fashion who have lower probability of upstaging and better outcomes.
Sorafenib treatment of Asian patients with advanced renal cell carcinoma (RCC) in daily practice: Subset analysis of the large non-interventional PREDICT study.
Authors: Ye Dingwei , Guo Jun , Lee Jae-Lyun , Zhou Ai-Ping , Huang Yiran , Hu Zhiquan , Fu Cheng , Liu Jiyan , Qi Lin , Li Hanzhong , Zou Qing , Hong Sung Joon , Stauch Kathrin , Böckenhoff Annette , Kim Gyunji , Zhang XiaoJing , Ahn Hanjong , Ma Jianhui
Published: March 2020

4628

Background: Previous studies with sorafenib in Asian patients with advanced RCC were relatively small and used strict entry criteria. Here we investigated safety and efficacy in a large subset of Asian patients in the prospective, non-interventional PREDICT study of sorafenib in routine practice (NCT 00895674). Methods: Patients were eligible based on a diagnosis of advanced RCC and the decision by the investigator to prescribe sorafenib under compliance of the local product label. Tumor status, patients’ performance and physician assessment of efficacy and tolerability were collected up to 12 months. Results: Between Jan 2007 and June 2010, 1092 patients were enrolled in China (n=1033), South Korea (n=55), the Philippines (n=3) and Indonesia (n=1). In the efficacy population (n=909), baseline characteristics were: 71% male; 89% <70 years old; 89% clear cell histology; 78% prior nephrectomy; 56% prior systemic therapy; 16% high MSKCC risk; 35% ECOG PS ≥2; 5% brain metastases. Overall, 19% of patients had ≥1 concomitant disease at baseline; the most frequent concomitant diseases were hypertension (14%) and diabetes (6%). Initial sorafenib dose was 800 mg daily in 97% of patients, of whom 91% were also receiving 800 mg daily as last dose. Median duration of sorafenib treatment was 9.7 months (range 0.2–24.1), and in clinically relevant subgroups was as follows: treatment-naïve, 9.7 months; high MSKCC risk, 9.3 months; brain metastases, 8.4 months; age ≥70 years, 7.6 months; ECOG PS 2, 9.7 months; ECOG PS 3, 6.1 months. At last follow up, 63% of physicians reported good/very good efficacy and 59% good/very good tolerability. Sorafenib was well tolerated; <2% of the safety population (n=1022) reported serious drug-related adverse events (SDRAEs) and only 3% discontinued due to DRAEs. In all, 35% of patients reported a DRAE, with the most frequent being hand-foot skin reaction (21%), diarrhea (7%), rash (7%), alopecia (5%), hypertension (3%). Conclusions: In this large subset of Asian patients with advanced RCC treated in daily practice settings, sorafenib was well tolerated and provided benefit, including in clinically relevant patient subgroups.
Overall survival (OS) benefit with sipuleucel-T by baseline PSA: An exploratory analysis from the phase III IMPACT trial.
Authors: Chodak Gerald , Schellhammer Paul F. , Whitmore James Boyd , Sims Robert Brownell , Kantoff Philip W.
Published: March 2020

4648

Background: Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. In the IMPACT trial, sipuleucel-T showed a 22.5% reduction in risk of death vs the control group (hazard ratio [HR]=0.775 [95% CI 0.614, 0.979]; P=0.032). A pre-specified subgroup analysis for baseline prognostic variables showed homogeneous treatment effects consistently favoring sipuleucel-T. In patients (pts) with baseline PSA below vs above the median, there was a trend toward greater treatment effect (HR=0.685 vs. 0.865). In this exploratory analysis, we further sub-divide baseline PSA into quartiles to evaluate potential treatment effect patterns. Methods: The analysis included all randomized pts from IMPACT (n=512). Pts were categorized by baseline PSA quartile (Table), ECOG PS and by median for other baseline prognostic variables (i.e., LDH, PAP, ALP in bone-only disease, and Hgb). Median OS and HR were estimated using Kaplan-Meier and Cox models, respectively. Results: Increasing baseline PSA quartile was associated with markers of advanced disease. HRs suggest a consistent treatment effect in all subsets, although there is inadequate power to show significant results within each quartile. There was a trend toward an increased magnitude of treatment benefit in pts with a lower baseline PSA (Table). Results for other baseline prognostic variables also suggest a trend toward greater benefit in subjects with better prognostic features. However, results for baseline Hgb indicated an opposite trend. Conclusions: Although not adequately powered for significance, the results of this analysis support a consistent OS benefit with sipuleucel-T across PSA quartiles. The greater magnitude of benefit in pts with lower baseline PSA suggests that pts with less advanced disease may benefit more from treatment with sipuleucel-T. [Table: see text]
Correlation of UHRF1 expression in primary prostate cancer patients with adverse prognosis.
Authors: Roggero Enrico , Sarti Manuela , Pinton Sandra , Thalmann George , Catapano Carlo , Bonapace Ian Marc , Carbone Giuseppina
Published: March 2020

4661

Background: Cancer of the prostate is a leading cause of cancer death in western countries. There is a great need to understand the clinical course of the disease and to distinguish the indolent tumors from those with aggressive behavior. Epigenetic mechanisms play an essential role in cancer initiation and progression. Our groups have recently provided evidence that over-expression of UHFR1 (ubiquitin-like with PHD and ring finger domain) leads to prostate cancer progression by activating a robust epigenetic switch involving silencing of a network of tumor suppressor genes. The purpose of this study was to evaluate in a clinical setting the prognostic impact of UHFR1 expression. Methods: In a series of 225 eligible patients (median age 63 years, range 44-75) with prostate cancer treated in a single institution with prostatectomy between 1990 and 1999 we evaluated the tumor nuclear expression of UHRF1 by immunohistochemistry (IHC). Clinical and histological data of the series were also reviewed. The UHFR1 expression (evaluated in tissue microarrays by immunohistochemistry) and prognostic factors were analyzed using univariate analyses and multivariate logistic regression analysis to identify association with overall survival (OS). Results: The median FU for the series was 137 months (range 1-229), eighty-one patients died (median FU 85 months). In Ninety-seven patients (43%) the UHRF1 expression was positive. In univariate analyses Gleason Score (<7 vs 7-9), Stage Risk Group (TNM Stage <III vs Stage III and/or N+) and UHFR1 expression (negative vs positive) were significant prognostic factors for OS with p-value <0.0001. In multivariate analyses Gleason Score, Stage Risk Group and UHFR1 expression were independent predictors for OS with respectively HRs of 2.77 (95% CI 1.72-4.46) p<0.0001, HRs of 1.96 (95% CI 1.14-3.37) p=0.014 and Hrs 1.35 (95% CI 1.02-1.78) p=0.030. Conclusions: Our results indicate that expression of UHFR1 protein, independently from historical prognostic factors, is linked with adverse prognosis for overall survival in a homogeneous primary prostate cancer treated group with long-term follow-up.
Detection of disseminated tumor cells in bone marrow as an independent prognostic factor in primary ovarian cancer patients.
Authors: Wimberger Pauline , Banys Malgorzata , Kasimir-Bauer Sabine , Hartkopf Andreas D. , Krawczyk Natalia , Marth Christian , Kimmig Rainer , Neubauer Hans , Wallwiener Diethelm , Fehm Tanja N.
Published: March 2020

5042

Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM)of breast cancer patients is associated with poor outcome. Recent studies demonstratedthat DTC may serve as a prognostic factor in ovarian cancer.The aim of our study was to evaluate the impact of BM status on survival in a large cohort of ovarian cancer patients. Methods: 365 patients with primary ovarian cancer were included into this three-center prospective study. BM aspirates were collected preoperatively from iliac crest. Disseminatedtumor cells were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and by cytomorphology. Patient outcomes were evaluated using a multivariable Cox regression model. Results: Disseminated tumor cells were detected in 28% of all BM aspirates. The number of CK-positive cells ranged from 1 to 42 per 2x106 mononuclear cells. DTC status did not correlate with any of the established clinicopathogical factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 mo, 95% CI: 35 – 67 mo versus 32 mo, 95% CI: 22 – 42 mo; p = 0.003). However, disease-free survival was not related to DTC-positivity. In the multivariable analysis, BM status, FIGO stage, nodal status, resection status and age were independent predictors of reduced overall survival. Interestingly, a subset of DTCs may have stem cell properties since a subset of these cells (128 out of 228 cases) were SOX2 positive, which is an embryonic stem cell marker. Conclusions: Tumor cell dissemination into bone marrow is a common phenomenon in ovarian cancer. DTC detection has the potential to become an important biomarker for prognostication and may be included as a therapeutic target in future concepts.
Effect of BRCA mutation on prognosis in patients with ovarian cancer: A systematic review and meta-analysis.
Authors: Valachis Antonis , Polyzos Nikolaos P. , Zavos Apostolos , Mauri Davide , Lind Pehr A.
Published: March 2020

5066

Background: To investigate whether the germ-line mutations of BRCA 1 and 2 in patients with ovarian cancer are associated with disease outcome. Methods: A systematic search of the literature was performed using search terms related to BRCA, ovarian cancer and prognosis. Studies were considered eligible if they reported the outcome of ovarian cancer in patients with BRCA 1 and/or 2 mutations compared with patients with sporadic ovarian cancer or / and no BRCA mutation. Cohort and case-control designs were included. Pooled Hazard Ratios (HR) were estimated with fixed or random effects models, depending on between-studies heterogeneity. Results: Of 2,340 titles identified, 26 articles met the inclusion criteria. Of these, 6 studies were excluded from the analysis due to duplication of results (n=1) and lack of data to calculate HR (n=5). Patients with BRCA 1 or 2 mutations had better survival compared with control group both in cohort (HR: 0.58, 95% Confidence Interval (CI) 0.42-0.79, p-value 0.0005) and in case-control (HR: 0.65, 95% CI 0.45-0.93, p-value = 0.02) studies. When only patients with BRCA 1 mutation were analyzed, the survival benefit remained significant (HR: 0.67, 95% CI 0.53-0.85, p-value = 0.001). Furthermore, the differential survival benefit of the mutation groups was even more evident among patients with BRCA 2 mutation (HR: 0.43, 95% CI: 0.30-0.63, p-value < 0.0001). A direct comparison of patients with BRCA 1 vs. BRCA 2 mutations (4 studies) revealed a significantly better survival for BRCA 2 mutation carriers (HR: 0.53, 95% CI: 0.33-0.85, p-value = 0.009). Conclusions: Our results confirm the hypothesis that BRCA status is a prognostic factor in patients with ovarian cancer. Based on these results, the use of BRCA status as a stratifying factor in therapeutic ovarian cancer trials seems to be fully justifiable. The stronger association between survival and BRCA 2 mutation, compared with BRCA 1, suggests a different nature of the dysfunction of these 2 genes.
Association of SNP genotype in ABCB1 with completion of intraperitoneal chemotherapy in ovarian and primary peritoneal cancer.
Authors: Enderica Gonzalez Sergio , Weroha Saravut John , Maurer Matthew J. , Moyer Ann M. , Goode Ellen L. , Rider David N. , Qin Rui , Haluska Paul , Costello Brian Addis
Published: March 2020

5077

Background: A standard of care (SOC) for the adjuvant treatment of ovarian and primary peritoneal cancer is a platinum-based intravenous (IV) chemotherapy doublet. Intraperitoneal (IP) chemotherapy is also a SOC, but the high incidence of grade 3/4 adverse events has limited its acceptance among clinicians. To identify genetic markers for completion of IP chemotherapy, we analyzed SNPs in four genes known to play a role in metabolism of platinum or taxane drugs. Methods: Patients diagnosed with primary or recurrent stage III or IV epithelial ovarian or primary peritoneal cancer who had primary or secondary debulking surgery at Mayo Clinic (Rochester, MN) between January 2007 and February 2009 followed by IP chemotherapy were included in this study. A cycle was defined as IV paclitaxel (135mg/m2) on day one, IP cisplatin (100mg/ m2) on day two, and IP paclitaxel (60mg/ m2) on day eight. With prior consent from the patient, peripheral blood was obtained before treatment for extraction of germline DNA. Using a custom Illumina BeadXpress 96-plex panel, SNPs in GSTM1 (N=7), ABCB1 (N=57), CYP3A4 (N=7), and CYP2C8 (N=25) were genotyped. The association between SNPs in these subsets of genes and completion of IP chemotherapy was analyzed using linear regression. Results: Thirty-seven patients were included in this study and 16 (43.2%) completed IP chemotherapy. Twenty-two out of the fifty-seven ABCB1 SNP’s were associated with the number of cycles (p<0.15). There were no significant associations for GSTM1, CYP3A4 and CYP2C8 SNP’s. The minor A allele at missense SNP rs2229109 in the ABCB1 gene was present in five (31.2%) who completed treatment and only one (4.8%) who did not (p<0.007). However, the later was due to catheter complication. There was no association between rs2229109 and overall or progression-free survival. Conclusions: Our findings suggest that SNP rs2229109 in ABCB1 gene is associated with completion of IP chemotherapy, and potentially, less toxicity from chemotherapy. Thus, these patients may be optimal candidates for IP chemotherapy. Further studies in a larger population are needed.
Pair box (PAX8) protein to predict disease recurrence and its association with outcome in women with endometrial cancer: A retrospective study of 229 patients.
Authors: Samrao Damanzoopinder , Wang Dan , Mhawech-fauceglia Paulette
Published: March 2020

5091

Background: Pax-8 is a member of the pair-box (PAX) family of transcription factor genes and it has been found to be overexpressed in numerous cancer cell lines including ovarian and endometrial. Possibly, inhibition of Pax8 activity may even have an impact on cancer treatment. However the role of Pax8 in human endometrial cancer has not yet been explored. Thus, the aim of this study is to determine its predictive value in disease outcome of endometrial cancer. Methods: 229 patients with available clinical data and paraffin-embedded tissue were available for review and analysis. The clinical parameters used for modeling were age, histologic subtypes, myometrial depth of invasion, lympho-vascular invasion (LVI), FIGO grade, lymph nodes positive, recurrence, disease status, recurrence time and survival time. To test the association between Pax8 and the clinical parameters, Fisher’s exact test was performed. For survival analysis, Kaplan-Meier method was performed. Results: We found a strong association between PAX8+ and high tumor grade (p=0.002), LVI + (p<0.018), and type II tumor subtype. Patients with tumor expressing Pax8 were more likely to present with shorter OS and DFS p= 0.00096 and p=0.018 respectively. There was an association of PAX8 with OS (p=0.01486) with 5-years OS probability of 80.04% for patients with Pax8- and 55.9% for patients with Pax8+. There was also an association of PAX8 and DFS probability (p=0.02028) with 5-years DFS probability was of 72.12% for patients with Pax8- versus 49.88% for patients with Pax8+ expression. Conclusions: Pax8 is a reliable marker in endometrial cancer and its overexpression can predict poor outcome.