bluuebunny/crossref_metadata_2025 huggingface dataset:
The regulation of clear cell renal cancer cells proliferation and tyrosine kinase inhibitors responsiveness by tumor micro-environmental factors.
Authors: Czarnecka Anna Malgorzata , Solarek Wojciech , Matak Damian , Khan Mohammed Imran , Kornakiewicz Anna , Szymanski Lukasz , Czarnecka Karolina , Lewicki Slawomir , Zdanowski Robert , Szczylik Cezary
Published: February 2017

488

Background: Tumor microenvironment is a complex network of multiple cell types, paracrine and endocrine signaling molecules, ECM and physical factors, which orchestrate the fate of tumor progression. In the field of ccRCC little attention has been paid to non-immunologic factors in tumor niche. Objectives of this study include the analysis of hypoxia, triiodothyronine (T3), insulin, insulin-like growth factor-1 and -2 impact on ccRCC cells. The effect of above mentioned tumor niche factors on TKI activity on ccRCC cells was to be quantified. The study was initiated as ccRCC cells are known to harbor disrupted hypoxia response and TRbeta (TRβ) - T3 receptor - functions as a tumor suppressor with tissue hypothyroidism involved in maintaining a proliferative advantage, whereas hypothyroidisms was defined as biomarker of sunitinib treatment efficacy. Moreover obesity and diabetes (DM2) are considered risk factors for ccRCC and high IGF-I expression is associated with poor long-term patient survival. This research aims to find molecular background for clinically relevant observations. Methods: ccRCC cells from primary and metastatic tumors (ATCC, MSK collections) along with cancer progenitor cells (CD133+) were cultured in normoxic or hypoxic conditions; in defined media supplemented with T3, IN, IGF, TRβ inhibitor and TKIs (sunitinib, axitinib). Cell proliferation was evaluated using AlamarBlue and MTT. Colony formation potential was evaluated. TRβ gene expression was measured with RealTime-RT PCR and sequenced under standard protocol. Normal kidney proximal tube cells were used as negative control. Results: ccRCC TKI responsiveness is limited by hypoxia, at the same time tumor cell proliferation may be promoted by T3, IN and IGF. Colony formation potential of ccRCC cells under TKI treatment in hypoxic conditions is downregulated. Conclusions: Multiple micro-environmental factors modify the proliferation and/or differentiation of ccRCC cell populations. Understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment should aid the identification of novel targets for improving TKIs clinical management.
Sunitinib versus sorafenib as first-line therapy for patients with metastatic renal cell carcinoma with favorable or intermediate MSKCC risk factors: A multicenter randomized trial, CROSS-J-RCC.
Authors: Tomita Yoshihiko , Naito Sei , Sassa Naoto , Takahashi Atsushi , Kondo Tsunenori , Koie Takuya , Obara Wataru , Kobayashi Yasuyuki , Teishima Jun , Takahashi Masayuki , Matsuyama Hideyasu , Ueda Takeshi , Yamaguchi Kenya , Kishida Ken , Shiroki Ryoichi , Saika Takashi , Nobuo Shinohara , Oya Mototsugu , Kanayama Hiro-Omi
Published: February 2017

502

Background: Sorafenib (SO), an earlier introduced kinase inhibitor, and sunitinib (SU), a standard first-line treatment drug for metastatic renal cell carcinoma (mRCC), were associated with progression-free survival (PFS) of 5.7 and 11 months (M) in independent clinical trials, respectively. We compared PFS of first-line SU and SO in a multicenter, randomized, open-label, phase III trial. Methods: Patients with untreated, measurable (by RECIST v1.1) clear-cell mRCC stratified according to MSKCC risk criteria, nephrectomy, and institution were randomized in 1:1 to receive SU (50 mg qd 4 wks on-2 wks off) or SO (400 mg bid). The calculated sample size was 59/group for α = 0.05, β = 0.10, and a censoring rate of 15%. Results: Of 124 enrolled patients, from Feb. 2010 to Jul. 2012, from 39 institutions, 120 were evaluable (SU, 57 and SO, 63). Patient baseline characteristics in the SU vs SO groups were as follows: favorable risk, 21% vs 22%; presence of stable brain metastasis, 8.8% vs 1.6% and with nephrectomy, 88% vs 89%. Median PFS (mPFS) was 8.7 and 7.0 M in the SU and SO groups, respectively (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.42–1.08; p= 0.095). mPFS was 31.2 and 6.2 M (HR 0.27, 95%CI 0.08–0.90; p = 0.023) in the favorable risk group, 11.9 and 6.5 M (HR 0.31, 95%CI 0.14–0.69; p = 0.035) in patients with T1 or T2 primary tumors, and 11.6 and 7.0 M (HR 0.41, 95%CI 0.36–0.98; p = 0.038) in those without brain metastasis, in the SU and SO groups, respectively. Objective response rates for SU group was 35.3%; SO was 27.8% (p = 0.407). Overall survival was not reached. The most common adverse events (all grade, all cause) were hand-foot syndrome (SU vs SO, 71% vs 86%), hypothyroidism (70% vs 33%), fatigue (57% vs 40%), hypertension (55% vs 44%) and diarrhea (23% vs 38%). Conclusions: The primary endpoint was not achieved, but SU tended to be associated with longer mPFS in all cases. In patients with favorable risk, T1 or T2 primary tumors or in those without brain metastasis, significantly longer mPFS were noticed. Brain metastasis was associated with poorer prognosis even if it was stable at baseline. Clinical trial number: NCT01481870. Clinical trial information: 01481870.
Characterization of immune-related adverse events (irAEs) in a phase 3 trial of ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel mCRPC.
Authors: Beer Tomasz M. , Logothetis Christopher , Gerritsen Winald R. , Kwon Eugene D. , Scher Howard I. , Bossi Alberto , van den Eertwegh Alfons JM , Drake Charles G. , McHenry Brent , Liu David , Fizazi Karim
Published: February 2017

52

Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]
Interest of percutaneous renal biopsy for small renal masses.
Authors: Ingels Alexandre , Barret Eric , Audenet Francois , Lunelli Luca , Prada Costa Guilherme , Validire Pierre , Lenoir Stephane , Rozet Francois , Galiano Marc , Sanchez-Salas Rafael , Cathelineau Xavier
Published: February 2017

539

Background: Assess CT-scan guided renal biopsies relevance in the management of small renal masses. Methods: Retrospective analysis from 01/2007 to 12/2012 of percutaneous CT-scan guided renal biopsies performed at our institution for patients harboring renal tumors. Exclusion criteria were presence of metastasis and/or >4cm tumors. Data analyzed were pathological outcomes, management of the tumors and complications from the procedure during the 30 days post-biopsies. Results: 119 patients underwent a renal biopsy during this period. 79 presented the selection criteria. Renal biopsies lead to a diagnosis in 70 cases (88.6%) and were non contributive in 9 cases (11.4%). Among contributive biopsies, there were 46 (66%) cases of cancer and 24 cases (34%) of benign tumors. During follow-up, 2 (2.5%) patients presented Clavien-Dindo grade I-II complications: 1 acute urinary retention and 1 subfebrile lumbar pain. Conclusions: The yield of CT-scan guided renal biopsies to define pathological features of small renal masses was of 88.6%. Morbidity of the technique is low. We consider renal biopsy as a relevant strategy to diagnose a small renal mass, to define the best treatment and to prevent morbidity from useless invasive surgical procedures. [Table: see text]
ABO blood group and risk of lethal prostate cancer.
Authors: Urun Yuksel , Wilson Kathryn M , Shui Irene M. , Giovannucci Edward L. , Wolpin Brian M. , Nguyen Paul Linh , Mucci Lorelei A. , Choueiri Toni K.
Published: February 2017

69

Background: An individual’s blood group is defined by variability in glycotransferases expressed on red blood cell surface; these ABO antigens are also highly expressed on epithelial cells. Previous studies have suggested associations between ABO blood group and increased risk of epithelial cancers including gastric, pancreatic, and ovarian; however, its relationship with risk of prostate carcinoma, and its aggressiveness remains unclear. Methods: We prospectively evaluated the association between ABO blood group and risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS) from 1996 to 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models with adjustment for other risk factors and prostate-specific antigen testing. Results: During 12 years of follow-up of 26,602 men, 2,703 cases of incident prostate cancer were documented, including 289 lethal cases (prostate cancer death or distant metastases). The frequency of ABO blood type was similar between men who developed prostate cancer (37% A, 7% AB, 13% B, and 43% O) and other participants (37% A, 8% AB, 12% B, and 43% O). On multivariate analysis, blood type was not associated with overall prostate cancer incidence. However, compared to men with blood group O, those with blood group AB were significantly less likely to develop lethal prostate cancer (multivariate-adjusted HR = 0.39 [95% confidence interval {CI} = 0.18-0.85]). There was no association between type B or A compared to O with lethal disease. ABO blood type was not significantly associated with the risk of advanced stage or high-grade cancers (Gleason score 8 to 10). Conclusions: Blood group AB was associated with a lower risk of lethal prostate cancer compared to blood group O. Further studies are needed to replicate these findings and to clarify possible biological mechanisms underlying this association.
Results from a phase 3, randomized, double-blind, multicenter, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy (ELM-PC 5 trial).
Authors: Dreicer Robert , Jones Robert , Oudard Stephane , Efstathiou Eleni , Saad Fred , De Wit Ronald , De Bono Johann Sebastian , Shi Yuanjun , Tejura Bindu , Agus David B. , Borgstein Niels Geert , Bellmunt Joaquim , Fizazi Karim
Published: February 2017

7^

Background: Orteronel is an investigational, non-steroidal selective inhibitor of 17,20-lyase; a key enzyme in the production of steroidal hormones. Methods: Eligible men with metastatic castration-resistant prostate cancer (mCRPC) had progressive disease (PD; radiographic or prostate-specific antigen), castrate levels of testosterone, and had received more than or equal to 360 mg/m2docetaxel within the prior 6 months. Prior orteronel, abiraterone, or ketoconazole was not permitted. Patients were randomized 2:1 to continuous 28-day cycles of oral orteronel 400 mg BID + prednisone 5 mg BID, or placebo + prednisone without regard to food. Primary endpoint: overall survival (OS); other key endpoints: radiographical progression-free survival (rPFS), 50% or more PSA decrease at 12 weeks, pain response at 12 weeks and safety (NCT01193257). Results: One thousand ninety nine patients were randomized.The study was terminated for failing to meet its primary endpoint: median overall survival (OS) was 17.0 months (95% CI 15.2, 19.9) in patients receiving orteronel versus 15.2 months (95% CI 13.5, 16.9) in those receiving placebo (HR: 0.886 [95% CI: 0.739, 1.062]; P=0.1898). Substantial regional differences were seen in OS benefit: median OS (orteronel vs. placebo) was 20.9 vs. 16.9 mo (HR: 0.889) in North America (n=112), 18.3 vs. 17.8 mo (HR: 1.048) in Europe (n=590), and 15.3 vs 10.1 mo (HR: 0.709) in the rest of the world (n=397). In the overall population, rPFS was significantly improved in the orteronel arm, with a median of 8.3 months vs. 5.7 months in the placebo arm (HR: 0.76 [95% CI: 0.653, 0.885]; P=0.00038). Drug-related adverse events (AEs; any grade) included (orteronel/placebo) nausea (30/16%), vomiting (23/8%), fatigue (17/11%), and diarrhea (16/9%); grade 3 or higher drug-related AEs included increased lipase (12/less than 1%), increased amylase (8/less than 1%), and fatigue (3/3%). Additional sub-analyses looking at potential factors that affected OS will also be reported. Conclusions: Whileorteronel + prednisone did not show a statistically significant overall OS improvement versus placebo + prednisone, rPFS findings and striking regional OS differences suggest that orteronel has clinically meaningful activity. Clinical trial information: NCT01193257.
The molecular and pathway characterization of patients with metastatic castration resistant prostate cancer (mCRPC) refractory to therapy with abiraterone acetate or enzalutamide: Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: Small Eric Jay , Youngren Jack , Beer Tomasz M. , Ryan Charles J. , Thomas George , Pourmand Nader , Reiter Robert Evan , Alumkal Joshi J. , Stuart Joshua M. , Evans Christopher P. , Gleave Martin Edwin , Chi Kim N. , Toschi Alex , Foye Adam , Lara Primo , Witte Owen ,   SU2C/PCF/AACR West Coast Prostate Cancer Dream Team
Published: February 2017

79

Background: Progressive metastatic castration resistant prostate cancer (mCRPC) has historically been challenging to biopsy and characterize on a molecular basis because of its bone tropism. Since mechanisms of resistance to androgen signaling inhibitors such as enzalutamide or abiraterone are not fully understood, both an unbiased and a targeted assessment of the molecular landscape of these patients is required. Methods: Patients (pts) with mCRPC undergo biopsy at one of five West Coast Prostate Cancer Dream Team (WCDT) clinical sites, using a uniform biopsy protocol, following central radiologic review. Tissue is both frozen, and formalin fixed/paraffin embedded (FFPE). Frozen tissue undergoes laser capture microdissection (LCM) for RNA seq, DNA seq, and array comparative genomic hybridization (aCGH). An RNA seq process was developed that allows using extremely small quantities of RNA (approximately 1 ng). FFPE tissue undergoes a CLIA-certified assessment of a 37-gene mutational panel, FISH for AR, and IHC for PTEN. Peripheral blood is collected for miRNA, immune responses, and CTC analysis including aCGH. Pathway assessment integrating clinical, RNA seq, DNA seq, aCGH data is undertaken using PARADIGM analysis. Results: Thirty six of 300 planned mCRPC pts have undergone a metastasis biopsy: 17 from bone, eight from liver, one from lung, and 10 from distant lymph nodes. Tumor is present in around 75% of the frozen specimens. To date, LCM has been undertaken in 11 samples, with RNA seq done in six, DNA whole exome seq in one, aCGH in four. FFPE tissue has been evaluated by mutational panel sequencing (n=9), FISH for AR (n=11), and IHC for PTEN (n=13). CTC have been isolated in 33 pts. aCGH has been successfully undertaken in paired CTC and biopsy specimens. Expression data from patients with full RNA sequencing have been analyzed by PARADIGM, with top disrupted pathways identified. Conclusions: Biopsies of mCRPC, including from bony sites, can be undertaken and used for molecular and pathway analysis. Sufficient tissue for unbiased and targeted assessment can be obtained. Linkage of results from these studies to the clinical characteristics of these patients will reveal important insights into mechanisms of resistance.
Predictors of choice of treatment in men with localized prostate cancer.
Authors: Konijeti Ramdev , Blonquist Traci M. , Halpenny Barbara , Hong Fangxin , Chang Steven L. , Trinh Quoc-Dien , Kibel Adam S. , Berry Donna Lynn
Published: February 2017

82

Background: The Personal Patient Profile-Prostate (P3P) is an Internet-based decision support program for men with newly diagnosed prostate cancer (CaP), which significantly reduced decisional conflict in treatment selection in a multicenter trial (2007 to 2009). We performed an ad hoc analysis of data from the trial (including five sites in Washington, Pennsylvania, Georgia, and Texas) to determine factors associated with initial treatment selection (watchful waiting [WW], external radiation [XRT], brachytherapy, or surgery [RP]) in men with localized CaP. Methods: Baseline patient characteristics measured for 462 patients included age, income (less than $35,000 vs. more than $35,000), employment (working vs. not ), relationship status (married/partnered vs. not), state and trait anxiety, amount of confidence in a particular physician (a lot vs. less), and whether the patient was seen by a urologist only or both a urologist and radiation oncologist. Univariate and multivariable logistic regression were used to identify predictors of initial treatment choice within 6 months of diagnosis. Results: Common treatment choices were RP (48%), XRT (21%), and WW (15%). In both univariate and multivariable analyses, men seen by a urologist only were more likely to choose WW (p=0.03 and p=0.02, respectively); employed men were less likely to choose WW (p=0.01 and p=0.02, respectively). In multivariable analysis, married/partnered men were more likely to choose surgery (p=0.03); anxiety was not statistically significantly associated with any treatment choice. Conclusions: Our findings suggest that treatment choice is related to social infrastructure and type of specialist seen. These findings should guide counseling of patients with newly diagnosed localized CaP. Further studies related to the role of sociodemographic characteristics and access to specialty care in initial treatment choice are warranted.
A phase II trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC).
Authors: Petrylak Daniel Peter , Smith David C. , Appleman Leonard Joseph , Fleming Mark T. , Hussain Arif , Dreicer Robert , Sartor A. Oliver , Shore Neal D. , Vogelzang Nicholas J. , Youssoufian Hagop , Olson William C. , Stambler Nancy , Huang Kathleen , Israel Robert Joseph
Published: February 2017

83

Background: The abundant expression of prostate-specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA antibody drug conjugate (ADC) is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized and cleaved by lysosomal enzymes releasing free MMAE causing cell cycle arrest and apoptosis. We enrolled 70 patients (pts) in a phase II trial of PSMA ADC in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). Methods: Pts with progressive mCRPC following taxane and ECOG PS 0 or 1 were eligible. PSMA ADC was administered Q3 week IV for up to eight cycles. Safety, tumor response by prostate-specific antigen (PSA), circulating tumor cells (CTC), imaging, biomarkers and clinical progression were assessed. Dosing was initiated at 2.5 mg/kg and adjustment for tolerability was allowed. Results: Thirty five pts began treatment at 2.5 mg/kg. Due to neutropenia, the remaining 35 pts began at 2.3 mg/kg. All pts received prior docetaxel and abiraterone and/or enzalutamide. Forty one percent also received cabazitaxel. Adverse events (AEs) were consistent with what was seen in phase I; most common significant AEs were neutropenia (grade 4, 6.7% and 11.4% at 2.3 and 2.5 mg/kg, respectively) and peripheral neuropathy (grade 3 or higher, 6.7% (2.3) and 5.7% (2.5)). Two pts at 2.5 mg/kg died of sepsis. 43% of pts at 2.3 and 37% of pts at 2.5 had declines in CTC from 5 or more to less than 5 cells/7.5 ml blood and 57.1% (2.3) and 74.1% (2.5) had 50% or more CTC declines; 26.1% (2.3) and 16.1% (2.5) had PSA declines of 30% or more thus far. PSA and CTC responses were associated with higher PSMA expression on CTC and lower neuroendocrine (NE) markers. The CTC conversion rate (5 or more to less than 5) was approximately 80% in pts with low NE markers. Prior cabazitaxel or abiraterone and/or enzalutamide did not appear to affect response. Centralized assessments of images by RECIST of all pts are currently planned and will be presented. Conclusions: PSMA ADC at 2.3 mg/kg was generally well tolerated in pts with progressive mCRPC previously treated with taxane. Anti-tumor activity, CTC and PSA reductions were observed at 2.3 and 2.5 mg/kg. Updated safety, tumor response and radiographic assessments from the full cohorts of 2.3 and 2.5 mg/kg will be presented. Testing in taxane naïve pts is also ongoing. Clinical trial information: NCT01695044.
PD-1 blockade in tumors with mismatch repair deficiency.
Authors: Le Dung T. , Uram Jennifer N. , Wang Hao , Bartlett Bjarne , Kemberling Holly , Eyring Aleksandra , Skora Andrew , Azad Nilofer Saba , Laheru Daniel A. , Donehower Ross C. , Luber Brandon , Crocenzi Todd S. , Fisher George A. , Duffy Steve M , Lee James J. , Koshiji Minori , Eshleman James R. , Anders Robert A , Vogelstein Bert , Diaz Luis A.
Published: February 2017

LBA100

Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade. Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks. Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p < 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02). Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511.
Randomized, open-label, multicenter, phase III study of eribulin versus dacarbazine in patients (pts) with leiomyosarcoma (LMS) and adipocytic sarcoma (ADI).
Authors: Schöffski Patrick , Maki Robert G. , Italiano Antoine , Gelderblom Hans , Grignani Giovanni , Camargo Veridiana Pires De , Bauer Sebastian , Rha Sun Young , Chawla Sant P. , Blay Jean-Yves , Hohenberger Peter , D'Adamo David R. , Wang Benjamin , Chmielowski Bartosz , Le Cesne Axel , Demetri George D. , Patel Shreyaskumar
Published: February 2017

LBA10502

Background: In a phase II study of pts with advanced soft tissue sarcoma, 32% and 47% of pts with LMS and ADI respectively, treated with the microtubule dynamics inhibitor eribulin achieved progression-free survival (PFS) at the 12 wk timepoint (Schöffski et al. Lancet Oncol. 2011; NCT00413192). Based on these findings, this phase III study (NCT01327885) compared overall survival (OS) in pts with advanced LMS and ADI treated with eribulin or dacarbazine. Methods: Pts aged ≥ 18 yrs with advanced high/intermediate grade LMS or dedifferentiated, myxoid, round cell or pleomorphic variants of ADI incurable by surgery and/or radiotherapy were enrolled. Pts had ECOG status ≤ 2 and had received ≥ 2 standard systemic treatment regimens including an anthracycline. Pts were randomized 1:1 to eribulin (1.4 mg/m2, IV on D1 and D8) or dacarbazine (850–1200 mg/m2, IV on D1) every 21 days until disease progression. Primary endpoint was OS. Secondary endpoints included PFS, PFS rate at Wk 12 and safety. Results: Overall, 452 pts (67% female; 79% < 65 yrs) were randomized (228 eribulin; 224 dacarbazine). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI 0.618–0.954; P= 0.017). PFS was 2.6 months in both arms (HR = 0.877, 95% CI 0.710–1.085; P= 0.229). PFS rate at Wk 12 was 33% and 29% for eribulin and dacarbazine, respectively. In eribulin and dacarbazine arms, respectively, 26% and 14% of pts required dose reductions and 8% and 5% discontinued due to treatment-emergent adverse events (TEAEs). TEAEs were more frequent in eribulin than dacarbazine arm, including neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%) and alopecia (35% vs. 3%); as were TEAEs of grade 3 (63% vs 53%), grade 4 (26% vs 20%), and fatal TEAEs (4% vs 1%). Thrombocytopenia was more frequent in dacarbazine than eribulin arm (28% vs 6%). Conclusions: This phase III trial of eribulin trial met its primary objective of OS benefit in pretreated pts with advanced LMS or ADI. Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. Funding Source: Eisai Inc. Clinical trial information: NCT01327885.
NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases.
Authors: Brown Paul D. , Asher Anthony L. , Ballman Karla V. , Farace Elana , Cerhan Jane H , Anderson S. Keith , Carrero Xiomara W. , Barker Frederick G. , Deming Richard L. , Burri Stuart , Menard Cynthia , Chung Caroline , Stieber Volker W. , Pollock Bruce E. , Galanis Evanthia , Buckner Jan C. , Jaeckle Kurt A.
Published: February 2017

LBA4

Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. Methods: Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93). Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. Clinical trial information: NCT00377156.
A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521).
Authors: Sandler Howard M. , Hu Chen , Rosenthal Seth A. , Sartor Oliver , Gomella Leonard G. , Amin Mahul , Purdy James , Michalski Jeff M. , Garzotto Mark , Pervez Nadeem , Balogh Alexander G. , Rodrigues George , Souhami Luis , Reaume M. Neil , Williams Scott G. , Hannan Raquibul , Horwitz Eric M. , Raben Adam , Paulus Rebecca , Shipley William U.
Published: February 2017

LBA5002

Background: High-risk, localized prostate cancer (PCa) patients have a relatively poor prognosis. We hypothesized that the addition of adjuvant docetaxel and prednisone to long-term (24 month) AS and radiation therapy (RT) would improve overall survival (OS). Methods: RTOG 0521 opened December 2005 and closed August 2009 with targeted accrual of 600 cases. It was designed to detect improvement in 4-year OS from 86% to 93% with a 51% hazard reduction (HR = 0.49). Under a 0.05 1-sided type I error and 90% power, at least 78 deaths were required to analyze the OS endpoint. Patients had 1) Gleason (Gl) 7-8, any T-stage, and PSA > 20, or 2) Gl 8, ≥ T2, any PSA, or 3) Gl 9-10, any T-stage, any PSA. All had PSA ≤ 150. RT dose was 75.6 Gy. CT consisted of 6, 21-day cycles of docetaxel + prednisone starting 28 days after RT. Results: Of 612 enrolled, 50 were excluded for eligibility issues, leaving 562 evaluable. Median age = 66, median PSA = 15.1, 53% had Gl 9-10, 27% had cT3-4. Median follow-up = 5.5 yrs. 4-yr OS rates were 89% [95% CI: 84-92%] for the AS+RT arm and 93% [95% CI: 90-96%] for the AS+RT+CT arm (1-sided p = 0.03, HR = 0.68 [95% CI: 0.44, 1.03]). There were 52 centrally-reviewed deaths in the AS+RT arm and 36 in the AS+RT+CT arm, with fewer deaths both due to PCa/treatment (20 vs 16) and due to other causes/unknown (32 vs 20) in the AS+RT+CT arm. 5-yr disease-free survival rates were 66% for AS+RT and 73% for AS+RT+CT (2-sided p = 0.05, HR = 0.76 [95% CI: 0.57, 1.00]). There was 1, Gr 5 unlikely-related adverse event (AE) in the AS+RT arm and 2, Gr 5 possibly/probably-related AEs with AS+RT+CT. Conclusions: For high-risk, localized PCa, adjuvant CT improved the OS from 89% to 93% at 4 years. Toxicity was acceptable. This trial was designed with a short OS assessment period and additional follow-up is warranted to determine the long-term benefit of CT to the current standard of care of long-term AS+RT. This project was supported by grants U10CA21661, U10CA180868, U10CA180822, from the National Cancer Institute and Sanofi with additional support from AstraZeneca for Australian site participation. Clinical trial information: NCT00288080.
Expression patterns of gpNMB in breast cancer (BC): Retrospective evaluation of tumor tissue from the phase II EMERGE study.
Authors: Yardley Denise A. , Melisko Michelle E. , Forero Andres , Bagley Rebecca G. , Zhang Joshua , Vahdat Linda T. ,   The EMERGE Study Group
Published: February 2017

129

Background: Glycoprotein NMB (gpNMB) is an internalizable transmembrane protein overexpressed in ~20% of BC. gpNMB promoted BC metastases in a murine model and is a poor prognostic marker in BC patients (pts) (Rose 2010). Glembatumumab vedotin (GV, CDX-011) is a novel antibody-drug conjugate targeting gpNMB+ cancer cells with the potent cytotoxin monomethyl auristatin E. In a Phase I/II and in the Phase II EMERGE study, GV was well-tolerated (treatment-related toxicity included rash, neutropenia, and neuropathy) with promising activity in gpNMB+ BC tumors including TNBC. In EMERGE, GV vs. investigator’s choice chemotherapy, demonstrated an objective response rate of 30% (7/23) vs. 9% (1/11) in pts with tumor gpNMB overexpression (gpNMB in > 25% of tumor cells); 18% (5/28) vs. 0% (0/11) in TNBC; and 40% (4/10) vs. 0% (0/6) in gpNMB-overexpressing TNBC. Improvements in progression-free survival (hazard ratio (HR) = 0.11) and overall survival (HR = 0.14) in gpNMB-overexpressing TNBC were noted. Methods: This retrospective analysis of the EMERGE study examined frequency of gpNMB overexpression by various baseline and disease characteristics. Tumors were centrally assessed by immunohistochemistry (IHC) and included data for 328 pts. Results: Tumor gpNMB overexpression was present in 21% (69/328) of screened and 40% (38/96) of TNBC pts. gpNMB overexpression was consistent in progesterone, estrogen, or HER2+ expressing tumors at rates of 12-15%. gpNMB overexpression was not observed among 17 lobular tumors, but was present in 21% (57/270) of ductal tumors. gpNMB overexpression was seen across organ sites, including lung (43%, 3/7), lymph node (31%, 12/39), chest wall (23%, 3/13), breast (21%, 44/209), bone (13%, 1/8), and liver (13%, 3/24). There were no apparent differences in gpNMB overexpression by age, race or disease setting (early vs. advanced) at tissue collection. Analysis is ongoing to determine if prior treatments may upregulate gpNMB expression. Conclusions: gpNMB overexpression in BC, especially in TNBC, appears consistent in archival primary and/or metastatic BC, regardless of age. A randomized multicenter study of GV in gpNMB overexpressing metastatic TNBC (METRIC) is ongoing. Clinical trial information: NCT01156753.
Association of PIK3CA mutation with response (ExRx) to cetuximab (C) in metastatic (met) triple-negative breast cancer (TNBC).
Authors: O'Shaughnessy Joyce , Ramos Corinne , Stephens Phil , Hoke Nicholas N , Palma Norma Alonzo , Levin Maren K. , Horiates Marina , Horak Christine E. , Wang Kai
Published: February 2017

151

Background: 10 to 17% of TNBCs harbor PIK3CA mutations (TCGA Nature 490:61, 2012; Khambata-Ford S. ASCO 2010, abst 1056). Here we report clinical history and molecular findings for a TNBC patient with loss of mutant PIK3CA in a C-refractory metastasis that was present in her primary BC, who has had an ExRx to C. Methods: Following IRB-approved informed consent, targeted NGS was performed on the pt’s FFPE primary TNBC and on a C-refractory recurrent lung metastasis at a CLIA-certified laboratory (Foundation Medicine) to characterize all classes of genomic alterations across 287 cancer-related genes. RPPA was performed at a CLIA-certified laboratory (Theranostics Health) where immunostaining with 24 antibodies was directed against HER1/2/3 pathway proteins and AR. Results: 37 yo woman presented in 2006 with grade 3 primary TNBC, infraclavicular LNs and lung metastases at 33 weeks gestation. There was no response to preop doxorubicin/cyclophosphamide and following delivery of a healthy baby, she was treated with irinotecan, carboplatin, and C (#NCT00248287) and had near complete response (CR) in her lungs and pathologic CR in breast. In 2008, after 20 mos on C, chest CT showed a new lung met which was resected and she remains disease-free on C alone. NGS: Primary BC: PIK3CA C420R, TP53 mutations, MCL1 amplification (amp), and RAD51D germline mutation; C-refractory lung met: TP53, MLL2 mutations, MCL1, MYC, KDM5A, CCNE1 amp and RAD51D germline mutation (loss of PIK3CAmutation confirmed). RPPA: Primary BC: p-AR S650 (3+); p-ERK (2+), and HER1, p-HER1, p-HER3, p-AKT, p-S6, p-4EBP1 (1+); C-refractory lung met: loss of p-ERK; p-HER1, p-4EBP1 (2+), and p-AR, p-AKT, p-mTOR (1+). PTEN: Primary BC: 60% cells positive by IHC MAb 6H2.1 (Cascade Biosciences). Conclusions: The pt’s ExRx to C was dependent on presence of PIK3CA mutation which was lost in the C-refractory lung met. Loss of RAD51D function may also have contributed (Liping L. Ca Res 68:9141, 2008). High p-AR expression did not preclude response to C. Activating PIK3CA mutations induce an EGFR/ERK paracrine signaling axis in TNBCs (Young CD. Mol Cell Proteomics 2015). A prospective trial of EGFR inhibition in PIK3CA-mutant TNBC is warranted.
Distance to nearest radiation facility and treatment choice in early stage breast cancer.
Authors: Acharya Sahaja , Michalski Jeff M. , Perkins Stephanie Mabry
Published: February 2017

73

Background: Breast conserving surgery followed by breast radiation (RT), collectively termed breast conserving therapy (BCT), is a recommended alternative to mastectomy (MT) for early stage breast cancer. Limited access to RT may result in more extensive surgical treatment. The purpose of this study is to assess the association between distance to nearest RT facility and MT use in a modern cohort of BCT eligible women. Methods: Women with Stage 0 – II breast cancer eligible for BCT diagnosed from 2004 – 2010 were identified from a US state registry. Distance from patient census tract to nearest RT facility census tract was calculated. Multivariate logistic regression was used to identify explanatory variables that significantly influenced MT use, adjusting for age, poverty, insurance, race, Hispanic ethnicity, marital status, diagnosis year, distance to nearest RT facility, T stage, N stage, ER/PR status and grade. Results: Of the 24,994 eligible women, 25.4% (n = 6,346) underwent MT and 74.6% (n = 18,648) underwent a breast conserving surgery. 32% of patients lived in a census tract that was > 5 miles from a RT facility. MT use increased with increasing distance to RT facility (24.5% at ≤ 5 miles, 26.5% at > 5 to < 15 miles, 29.5% at 15 to < 40 miles and 43% at ≥ 40 miles, p < 0.001). The likelihood of MT was independently associated with increasing distance to RT facility (Odds Ratio [OR]: 1.02 for every mile increase, 95% Confidence Interval [CI]: 1.01 – 1.02, p < 0.001). Compared to patients living ≤ 5 miles away from a RT facility, patients living 15 - < 40 miles away were 1.3 times more likely to be treated with MT (OR: 1.31, 95% CI: 1.15 – 1.51, p < 0.001), and those living ≥ 40 miles away were more than twice as likely to be treated with MT (OR: 2.29, 95% CI: 1.51 – 3.45, p < 0.001). When restricting the sample to women with T1 disease (n = 16,656), distance to RT facility remained a significant explanatory variable for MT use on multivariate analysis (p < 0.001). Conclusions: MT use in a modern cohort of women eligible for BCT is independently associated with increasing distance to RT facility. Measures to improve RT access should be explored to ensure universal opportunity for BCT.
Olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC): Alliance A221301, a randomized, double-blind, placebo-controlled trial.
Authors: Navari Rudolph M. , Qin Rui , Ruddy Kathryn Jean , Liu Heshan , Powell Steven Francis , Bajaj Madhuri , Dietrich Leah L. , Lafky Jacqueline M. , Loprinzi Charles L.
Published: February 2017

176

Background: The purpose of the study was to determine the effectiveness of olanzapine (OLN) for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC). Methods: A randomized, double-blind, phase III trial was performed in chemotherapy-naïve patients receiving cisplatin, > 70 mg/m2, or cyclophosphamide-anthracycline-based chemotherapy, comparing OLN to placebo in combination with aprepitant (APR), a 5-HT3 receptor antagonist (5-HT3), and dexamethasone (DEX). The OLN regimen was 10 mg of oral OLN, 125 mg APR, a 5-HT3, and oral DEX 12 mg pre-chemotherapy, day 1, and 10 mg/day of oral OLN and 8 mg DEX on days 2-4 post-chemotherapy plus 80 mg APR on days 2, 3 post-chemotherapy. The placebo (PLA) regimen was oral placebo, pre-chemotherapy, day 1, and on days 2-4 post-chemotherapy; the APR, 5-HT3, and DEX pre- and post-chemotherapy were identical to that used in the OLN regimen. Fosaprepitant (150 mg IV), day 1 was allowed for substitution for the oral aprepitant. Palonosetron, ondansetron, or granisetron were the permitted 5-HT3 options. Nausea was measured on a 0-10 visual analogue scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be”. No nausea was the primary endpoint and, complete response (no emesis and no use of rescue medications) was a secondary endpoint. Results: 401 patients (202 OLN, 199 PLA) were enrolled in the study. The proportion of patients who had no nausea was significantly greater for the OLN regimen compared to the PLA regimen for the acute period (24h post-chemotherapy) (74% vs. 45%, p < 0.0006), for the delayed period ( 24-120 h post-chemotherapy) (43% vs. 26%, p < 0.0006), and for the overall period (0-120 h) (39% vs. 22%, p < 0.0006). Complete response was significantly improved for the OLN patients compared to PLA patients for the acute (85% vs. 65%, p < 0.0001), the delayed (67% vs. 53%, p < 0.0078), and the overall periods (64% vs. 41%, p < 0.0001). There were no grade 3 or 4 toxicities. Conclusions: No nausea, the primary endpoint, and complete response, a secondary endpoint, were significantly improved with OLN, compared to PLA. Clinical trial information: NCT02116530.
Hematology and oncology fellows' attitude and knowledge in cancer pain management.
Authors: Mahmoud Fade A. , Arnaoutakis Konstantinos , Motwani Pooja , Schafer Liudmila N. , Mehta Paulette , Makhoul Issam
Published: February 2017

178

Background: The American Society of Clinical Oncology considers palliative care an integral part of cancer therapy. Our Hematology and Oncology fellowship at the University of Arkansas for Medical Sciences (UAMS) began a year-long palliative care curriculum to improve symptom management education. In this pilot study we evaluate fellows’ attitude and knowledge in cancer pain management before and after implementing a pain management curriculum. Methods: Hematology and Oncology Fellows were divided into three groups. Each group delivered a one hour lecture in pain management for a total of 3 didactic lectures. We adopted “Evidence based Practice of Palliative Medicine by Goldstein and Morrison” as the main textbook. Fellows answered a 30 item questionnaire to address attitudes and knowledge in pain management. Answers were scored using a 5 point Likert scale (1 = strongly disagree and 5 = strongly agree). Results: 11 fellows participated; six males, five females, median age 34 (R 28-40), one US graduate, and ten foreign graduates. More fellows felt comfortable managing acute (M = 4.3, SD = 0.48) compared to chronic (M = 3.8, SD 0.78) cancer related pain. Most believe that if they were taught the principle of pain management they would feel more comfortable managing pain (M = 4.6, SD = 0.51). Post pain management module, there was a statistically significant improvement in fellow’s knowledge in pain management in the setting of renal failure (P = 0.02) and bone pain (P = 0.006), and a trend towards statistically significant in both opioid rotation and conversion (P = 0.06). Fellows did poorly on opioid-drugs interaction and management of neuropathic pain. Fellows valued palliative medicine service as a great resource for their patients but most believe that they should not refer all their patients to palliative medicine for pain management. Conclusions: Pain management skills are eroding among Oncology fellows and efforts should be made to enhance symptom and pain management education in oncology training programs. This curriculum improved knowledge and self-efficacy in pain management and revealed areas for further improvement. More research is needed to address whether fellows use and apply pain management skills in the clinical setting.
Characteristics and outcomes of advanced cancer patients admitted to an acute palliative care unit (PCU) with severe dyspnea receiving high flow oxygen (HFO).
Authors: Delgado-Guay Marvin Omar , Rodriguez-Nunez Alfredo , Adegboyega Oluwatobi O , Newton Amy , Hernandez-Azmitia Maria Gabriela , Park Minjeong , Hui David , Bruera Eduardo
Published: February 2017

247

Background: Dyspnea is very complex and distressing symptom in patients with advanced cancer. The therapeutic goal of its symptomatic management is to relieve the patient’s breathlessness sensation. Limited literature has addressed the characteristics and clinical outcomes of advanced cancer patients with severe dyspnea receiving HFO admitted to PCU. Methods: We reviewed the records of 101 advanced cancer patients with dyspnea receiving HFO and 110 matched PCU inpatients with dyspnea receiving regular O2 flow (NoHFO) between January 1 to December 31, 2012. Demographics, frequency and intensity of symptoms at PCU admission and follow-up, and outcomes were recorded. Results: Median age: 60 years, range (51, 69). 56% were Male. White(71%), Hispanic(13%), African American(10%), Asian (4%). Primary cancer: Lung (27%), Gastrointestinal (19%), Hematological (18%), Breast (13%), Gynecological (6%). Dyspnea was present in all cases and it was related mainly to: lung involvement by cancer (53%), pneumonia (40%), Congestive Heart Failure (6%), COPD (8%). ECOG: 4. No significant difference in age, ethnicity and type of cancer, ECOG, and possible cause of dyspnea among both groups. HFO and NoHFO were started the same day of admission. Median ESAS symptoms (Interquartile range: IQR) for HFO was Pain 4.5 (2, 7) vs. 5 (3, 7) for NoHFO, p = 0.1423; fatigue [7(5, 8) vs. 7 (5, 8), p = 0.450]; depression [3 (1, 5) vs. 3.5 (2, 5), p = 0.81]; anxiety 7 (4, 9) vs. 6 (3, 8), p = 0.01; dyspnea [7.5( 6, 9) vs. 5 (3, 8), p < 0.0001]. Memorial Delirium Scale 5 (2, 15) vs. 7(2, 15), p = 0.77). Morphine Equivalent Daily Dose: 48 (36, 120) vs. 55 (30, 120), p = 0.72. The median difference among first and follow up ESAS was Pain 0 (-3, 1) vs. -1(-2, 1), p = 0.62; fatigue[(-2, 1) vs. 0 (-2, 0), p = 0.63]; depression [0 (-1, 1) vs. 0 (-1, 2), p = 0.93]; anxiety [0 (-2, 2) vs. 0 (-2, 2), p = 0.94; dyspnea [0( -1, 1) vs. -1 (-2, 1), p = 0.18]. Memorial Delirium Scale 0 (-1.5, 5.5) vs. 0 (-2, 3), p = 0.21).The median time (IQR) from HFO started to discharge was 10 days (6, 15) vs. 8.5 (5, 14) days for NoHFO, p = 0.07). The median time(IQR) from HFO started to Death was 10.5 (7, 19) vs. 13.5 (7, 26) days for NoHFO, p = 0.18. 77/101(76%) HFO patients vs. 56/110 (51%) NoHFO died at the hospital, p = 0.002. 24/101(23%) HFO patients were discharged alive weaned off HFO. The Odd ratio for hospital death in patients with HFO vs. NoHFO was 4.83 (95% CI: 1.72 – 13.59), p = 0.003. Conclusions: Severe dyspnea is significant at the end of life of advanced cancer patients. Patients with HFO require similar MEDD than NoHFO patients. Inpatient mortality is higher in patients with HFO. More research is needed.