bluuebunny/crossref_metadata_2025 huggingface dataset:
Independent validation of a genomic classifier in an at-risk population of men conservatively managed after radical prostatectomy.
Authors: Klein Eric A. , Li Jianbo , Stephenson Andrew J. , Yousefi Kasra , Kattan Michael W. , Magi-Galluzzi Cristina
Published: February 2017

16

Background: Patients with locally advanced prostate cancer after radical prostatectomy (RP) are at risk for clinical progression and by current guidelines are candidates for adjuvant radiation. While clinical trials comparing adjuvant radiation to observation demonstrated benefits for many of these patients about 50% men on the control observation arm did not progress. This study evaluated whether a validated genomic classifier ([GC], Decipher) for predicting metastasis can be used to identify high-risk patients that may be spared unnecessary secondary therapy. The objective was to validate GC predictions in an at risk population conservatively managed after RP. Methods: A case-cohort design was used to sample patients with either preop PSA>20 ng/mL, pT3, positive surgical margin or Gleason score 8 or more disease, treated at Cleveland Clinic with RP from 1987 to 2008. Patients with lymph node metastasis or neo-adjuvant or adjuvant treatment were excluded. Cases were defined as local recurrence and/or regional/distant metastasis confirmed by biopsy or positive CT/bone scan. Random sampling of the cohort, including all cases, yielded 220 patients. Tissue was available for 196 and GC scores were generated for 184 patients. AUC for survival data, weighted Cox regression analysis and cumulative incidence adjusting for competing risk were used to assess GC performance for predicting distant metastasis (DM) in comparison to the 2005 Stephenson nomogram. Results: GC had an AUC of 0.89 (95% CI 0.62-0.97) for predicting DM at 5 years post-RP. A combined GC-Stephenson model yielded an AUC of 0.81 (95% CI 0.62-0.96). GC was the predominant predictor in multivariable Cox analysis with an HR of 1.55 (95% CI 1.25-1.90) for a 10% increase in score. Patients with high (21.7%) and low GC scores (58.7%) had a 3.97 fold higher and 3.88 fold lower incidence of DM at 5 years than the intermediate group (19.6%), respectively. Conclusions: We present results of a second, blinded independent validation study of GC performance in a conservatively managed RP cohort. In an at risk population use of GC may further allow identification of men that may be safely spared adjuvant radiation therapy.
An open-label phase II clinical trial of the RXR agonist IRX4204 in taxane-resistant, castration-resistant metastatic prostate cancer (CRPC).
Authors: Kabbinavar Fairooz F. , Zomorodian Nazy , Rettig Matthew , Khan Faraz , Greenwald Daniel Reif , DiCarlo Brian , Davidson Sheldon J. , Patel Ravindranath , Pandit Lalita , Chandraratna Rosh , Sanders Martin
Published: February 2017

169

Background: IRX4204 is a potent, selective, oral small compound agonist of retinoid X receptor (RXR) nuclear receptor pathways. In preclinical studies IRX4204 synergizes with insulin-like growth factor binding protein-3, to induce apoptosis in human prostate cancer cells and was effective in reducing human prostate tumor burden in a murine xenograft model. The only prostate cancer patient in a phase I trial of IRX4204 trial manifested a sustained greater than 90% prostate-specific antigen (PSA) reduction and a PR lasting over seven months. These findings led to the current open label phase II trial of IRX4204 to evaluate safety and activity or futility, for treatment of advanced castration-resistant metastatic prostate cancer (CRPC). Methods: The trial enrolled 23 men with metastatic CRPC, who had failed a taxane or declined chemotherapy, with ECOG 0-2 with evidence of biochemical or radiographic progression on bone scan, CT and/or MRI. Patients continued with androgen blockade and had to have adequate organ function. Patients were deemed to have demonstrated benefit of IRX4204 treatment if they had PFS greater than 56 days, and/or a 50% PSA decrease, and/or PR or CR by RECIST. Futility defined as four or fewer patients demonstrating benefit in the planned enrollment of 37 patients. Patients received IRX4204 (20 mg/orally daily). PSA was checked Q4 weeks and radiographic assessments Q8 weeks. Radiographic, not PSA progression, was used to determine progression. Results: IRX4204 was well tolerated for up to 11 months. No drug related serious adverse events (SAE) have occurred. Manageable decreases in the thyroid-stimulating hormone (TSH) and increases in triglycerides, both known adverse effects of RXR agonists, have been observed. Protocol defined patient benefit was observed in 13 out of 23 (57%) patients. Progression-free survival (PFS) more than 56 days observed in 13 out of 23 (57%). PFS more than 112 days observed in 9 out of 23 (39%), range 113 to 330 days. PSA 50% response occurred in 3 out of 23 (13%), including one additional PSA 90% response. No objective responses have occurred. Conclusions: This study demonstrates that IRX4204 treatment of taxane-resistant CRPC is well tolerated, and provides an activity signal warranting further evaluation of IRX4204 as a treatment for chemo-refractory CRPC. Funding: Supported by Io Therapeutics, Inc. 1805 East Garry Ave., Suite 110, Santa Ana, 92705. Clinical trial information: NCT01540071.
Does Gleason score (GS) predict efficacy of abiraterone acetate (AA) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)? An analysis of AA phase 3 trials.
Authors: Fizazi Karim , Flaig Thomas W. , Ohlmann Carsten-Henning , Scher Howard I. , De Bono Johann Sebastian , Rathkopf Dana E. , Ryan Charles J. , Kheoh Thian San , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Molina Arturo , Stöckle Michael
Published: February 2017

20

Background: GS is strongly prognostic in localized PC but is less so in mCRPC (Halabi S, J Clin Oncol 2003; Armstrong AJ, Eur J Cancer 2010). Pts with high-risk localized PC and high GS who undergo radiation therapy benefit from long-term androgen deprivation therapy (Horwitz EM, J Clin Oncol 2008). In mCRPC, the impact of GS at initial diagnosis on response to AA therapy is unknown. We retrospectively evaluated efficacy outcomes in pts with mCRPC treated with AA plus prednisone (P) vs P alone in pivotal studies COU-AA-301 (post-docetaxel) and COU-AA-302 (chemo-naive) by GS (≥ 8 or < 8). Methods: 1,048 pts in COU-AA-301 and 996 in COU-AA-302 with mCRPC treated with AA 1 g + P 5 mg po BID or placebo + P had GS data at diagnosis. Efficacy end points evaluated: overall survival (OS), radiographic progression free survival (rPFS), and time to prostate-specific antigen progression (TTPP) (de Bono JS, NEJM 2011; Fizazi K, Lancet Oncol 2012; Ryan CR, NEJM 2013). Distributions and medians were estimated by the Kaplan-Meier method, and hazard ratio (HR) and 95% confidence interval were estimated by the Cox model. Results: Proportion of pts with GS ≥ 8 and GS < 8 was similar across treatment groups and studies. Outcomes by GS are summarized in the Table. Conclusions: GS (≥ 8 or < 8) at initial diagnosis was not predictive of treatment benefit of AA + P vs P alone in post-docetaxel and chemo-naïve pts with mCRPC, with both groups benefiting. In this era of novel androgen signaling targeted agents, GS may not be relevant in predicting efficacy with AA for pts with mCRPC. Clinical trial information: NCT00638690, NCT00887198. [Table: see text]
Circulating tumor cell (CTC) enumeration in patients with metastatic neuroendocrine prostate cancer (NEPC) and castration-resistant prostate cancer (CRPC).
Authors: Kaur Gurveen , Singh Beerinder , Beltran Himisha , Akhtar Naveed Hassan , Nanus David M. , Tagawa Scott T.
Published: February 2017

204

Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer. Circulating tumor cell (CTC) counts as measured by CellSearch are prognostic for large groups with metastatic prostate cancer (PC), but are not well described in NEPC. Methods: With institutional review board approval, we retrospectively identified patients with metastatic PC and available CTC enumeration (CellSearch methodology) and compared counts/7.5 mL blood and overall survival (OS), measured from the first recorded CTC count until death or last follow up. Entry criteria for clinical trials were used to define NEPC, including histology (small cell/neuroendocrine carcinoma or adenocarcinoma with more than 50% NE staining), serum chromogranin greater than 5x ULN and/or neuron specific enolase greater than 2x ULN, and/or predominant liver/brain metastases with lack of prostate-specific antigen [Beltran ASCO 2013, clinicaltrials.gov NCT01799278 ]. Frequency of detectable and unfavorable counts was tabulated and OS was compared across groups. Results: Sixty one patients were identified: 21 NEPC with median age 73.7 and 40 patients with castration-resistant prostate cancer (CRPC) with median age 73.9 over contemporary time periods 2009 to 2012. Median OS for the entire group was 22.6 months (mo), with a trend for shorter OS in NEPC (20.7 mo) than CRPC (22.7 mo), p=0.11. 47.6% of NEPC and 55% of CRPC had detectable CTC counts (p=0.58); 38.1% of NEPC and 40.0% of CRPC had greater than or equal to five CTCs (p=0.89). CTC counts of 0 to 4 versus greater than or equal to five were prognostic for both groups: NEPC with 0 to 4 CTCs had median OS of 22.6 versus 6.6 mo for CTCs greater than or equal to 5 (p<0.001) and CRPC with 0 to 4 CTCs median OS not reached (mean 40.6 mo) versus 11.2 mo for those with greater than or equal to five CTCs (p<0.001). Conclusions: Patients with NEPC have similar frequency of detectable and elevated CTC counts by CellSearch methodology as compared to an overall CRPC population. CTC counts are prognostic for both groups.
Prediction of prostate cancer Gleason score using a MRI-based nomogram.
Authors: Siddiqui Mohummad Minhaj , Rais-Bahrami Soroush , Truong Hong , Stamatakis Lambros , Walton-Diaz Annerleim , George Arvin , Rothwax Jason , Su Daniel , Shakir Nabeel , Wood Bradford J. , Merino Maria , Turkbey Baris , Choyke Peter L. , Simon Richard , Pinto Peter A.
Published: February 2017

255

Background: Gleason score grading is a cornerstone of risk stratification and management of patients with prostate cancer (PCa). The only reliable method to determine Gleason score remains by direct pathologic determination from a tissue specimen. In this work, we examine the feasibility of MRI and clinical patient characteristics to predict biopsy Gleason scores (bGS). Methods: We reviewed 143 men who underwent multiparametric prostate-MRI (MP-MRI) prior to any prostate biopsy from 8/2007 to 12/2012. Patient demographics, PSA, PSA density (PSAD), and imaging findings were assessed for association with PCa Gleason score on biopsy. Screen positive lesions (SPLs) were defined as lesions positive on T2W and DWI B-MRI images. Logistic regression modeling was used to assess association of the different parameters with bGS (no cancer, Gleason 6, 7, and ≥8). An optimized model for the prediction of bGS was determined and a nomogram was generated. Results: The mean age of the cohort was 60.7 ± 7.7 years and mean PSA of 6.8 ± 6.5 ng/ml. Factors associated with Gleason score include age, PSA, PSAD, prostate volume, MRI suspicion score, total lesions seen on MRI, number of SPLs. Various models were examined utilizing factors positively associated with Gleason score and the combination of PSA density with SPLs outperformed most other combinations. A nomogram was generated to derive the probability of No cancer, Gleason 6, 7, and ≥8 PCa using the inputs of PSAD and number of SPLs. The correlating c-indexes to Gleason 6, 7, and ≥8 PCa detection were 0.87, 0.87, and 0.92 respectively. When tested on the original cohort, the most probable nomogram generated Gleason score correlates with actual pathologic bGS findings in 53% of the men. The top two most probable nomogram Gleason scores contained the actual bGS findings in 81% of the men. Conclusions: PSAD combined with prostate MRI imaging characteristics shows potential for prebiopsy determination of prostate cancer Gleason score and presence. Further improvement in predictive performance of this test may ultimately yield a clinical tool that is of benefit for prebiopsy risk stratification of patients for PCa of clinical significance.
Frequent truncating mutations of the cohesin complex gene STAG2 in urothelial carcinoma of the bladder.
Authors: Solomon David A. , Kim Jung-Sik , Bondaruk Jolanta , Shariat Shahrokh F. , Wang Zeng-Feng , Elkahloun Abdel , Gerard Julia , Zhuang DaZhong , Zhang Shizhen , Robinson Brian D. , Rubin Mark A. , Volkmer Bjoern , Hautmann Richard , Kuefer Rainer , Netto George J. , Theodorescu Dan , Czerniak Bogdan , Miettinen Markku , Waldman Todd
Published: February 2017

290

Background: We have recently identified the cohesin complex subunit STAG2 as a gene that is somatically mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy (Solomon et al, Science, 2011 Aug 19). However, the complete tumor spectrum harboring STAG2 mutations and the clinical significance of STAG2 inactivation in cancer remain undefined. Methods: Immunohistochemistry was used to screen 2,214 tumors from each of the major tumor types for somatic loss of STAG2 expression. Sequencing of the STAG2 gene was performed on 111 urothelial carcinomas, and Affymetrix CytoscanHD Arrays were performed on STAG2 mutant tumors. Clinical data from 34 patients with non-muscle invasive urothelial carcinoma treated with transurethral resection and 349 patients with invasive urothelial carcinoma treated with radical cystectomy was correlated with tumor STAG2 status. Results: Complete loss of STAG2 expression was discovered in 52/295 urothelial carcinomas (18%), ranging from low grade papillary to high grade muscle invasive tumors. DNA sequencing revealed somatic truncating mutations of STAG2 in 23/111 urothelial carcinomas of the bladder, including 9/25 papillary non-invasive carcinomas (36%), 6/22 superficially invasive carcinomas (27%), and 8/64 muscle invasive carcinomas (16%). STAG2 mutation was found to be an early event in bladder tumorigenesis, frequently associated with alterations in p53 signaling, and often correlated with numerous chromosomal copy number aberrations per tumor. STAG2 loss in non-muscle invasive urothelial carcinomas treated with transurethral resection was found to be associated with increased disease-free survival (p=0.05), while STAG2 loss in invasive urothelial carcinomas treated with radical cystectomy was found to be associated with increased lymph node metastasis (p=0.03), earlier disease recurrence (p=0.04), and reduced cancer-specific survival (p=0.04). Conclusions: These results identify STAG2 as one of the most commonly mutated genes in bladder cancer, and demonstrate that STAG2 loss defines molecular subgroups of urothelial carcinomas with distinct clinical outcomes.
Phase I dose-escalated image-guided adaptive bladder radiotherapy study: Results of first dose cohort (68Gy).
Authors: Huddart Robert , McDonald Fiona , Hafeez Shaista , Warren-Oseni Karole , Taylor Helen , Thompson Alan , Khoo Vincent , Harris Victoria , McNair Helen , Mohammed Kabir , Thomas Karen , Jones Kelly , Dearnaley David Paul , Horwich Alan
Published: February 2017

291

Background: Prospective study assessing the safety of dose escalation in the treatment of localised muscle-invasive bladder cancer using image-guided adaptive radiotherapy (RT) with a reduced high-dose tumour volume. Methods: Radical RT was planned and delivered in 3 phases. Phase I was delivered to the empty whole bladder (10Gy 5#). Bladder variation assessed on phase I daily imaging was used to determine the adaptive approach for phase III (composite volume or plan of the day). Phase II was delivered to a tumour boost volume on a partially filled bladder (18Gy 9# if normal tissue dose-constraints were met, or to 14Gy 7# if they were not). The adaptive phase III (40Gy 20#) was delivered to the empty whole bladder. The primary endpoint was late RTOG toxicity. Results: Of the twenty-six patients recruited to 68Gy, 20 patients met the normal tissue constraints for dose escalation. For the phase III adaptive technique, 14 patients were treated with a composite volume approach and 12 with a plan of the day. At median follow-up of 24 months, 13 (65%) dose escalated patients remain alive and disease free. Within this dose cohort there has been 1 muscle invasive local recurrence, 1 superficial recurrence and 1 patient has developed metastases. 5 patients in the dose-escalated group have died; 3 from cardiac events, 1 from hospital acquired pneumonia and 1 from metastatic bladder cancer. 1 patient in the dose-escalated group has experienced grade 3 late toxicity (cystitis) occurring 24.6 months after the end of radiotherapy. Conclusions: Image-guided adaptive RT techniques with reduced high-dose volume allow tumour dose-escalation. Toxicity data to date suggest tolerability of 68Gy. Local disease control rates are promising. Trial recruitment continues at 70Gy using intensity modulated radiotherapy technique to deliver a simultaneous integrated boost. Clinical trial information: 7653.
Using microRNA (miRNA) profiling to differentiate noninvasive and muscle-invasive from metastases of transitional cell carcinoma of the urinary bladder (TCC-UB).
Authors: Ogbata Obiageli Uchenna , Yang Chuan , Pfeffer Lawrence , Ojukwu Somtochukwu , Gaines Grant , Pillappa Raghavendran , O'Brien Thomas , Weir Alva Bowen , Mahadevan Daruka
Published: February 2017

338

Background: Altered miRNA expression contributes to the pathogenesis of urologic malignancies, including bladder cancer (BC). Individual miRNAs are known to regulate multiple signaling pathways in BC. We hypothesized that identifying miRNA gene expression profiles (GEP) in TCC-UB in the localized (non-invasive Vs invasive) and metastatic setting will help identify predictive and prognostic biomarkers within oncogenic signaling pathways, and novel therapeutic targets. Methods: We conducted a retrospective review of pathology reports of patients with TCC-UB from 2005 - 2013. The samples were categorized into non-invasive, muscle-invasive and metastatic sites. Normal urothelium was used as controls. Bone metastasis and tumors with squamous differentiation were excluded. RNA was extracted from Formalin Fixed Paraffin Embedded (FFPE) tissue blocks and assessed with Nanostring - nCounter miRNA expression assays. The Student t test was used to analyze the data. P value of < 0.05 was considered statistically significant. Results: 36 FFPE tumor samples were identified and analyzed – 18 muscle-invasive (MI), 9 non-invasive (NI), 7 metastatic (M) and 2 normal urothelium (C). Of the over 600 miRNA assessed by the Nanostring microarray, miR21 and 494 were consistently up-regulated, while miR451a, 144-3p, 363-3p, 15b-5p, 200a-3p, 137, 429 were downregulated. Conclusions: MicroRNA profiling differentiates non-muscle invasive versus muscle-invasive BC from metastatic sites. The data provides insights into molecular alterations that will help distinguish signaling pathways of bladder carcinogenesis such as FGFR, PI-3K, STAT-3 and p53. Identified molecular targets will provide an effective and promising strategy to be evaluated in BC cell lines. [Table: see text]
Activity of pazopanib in chemo-resistant patients with germ cell tumors (GCT): First results of the open-label, single-group, phase II PAZOTEST-01 trial.
Authors: Giannatempo Patrizia , Nicolai Nicola , Farè Elena , Raggi Daniele , Piva Luigi , Biasoni Davide , Catanzaro Mario , Torelli Tullio , Stagni Silvia , Maffezzini Massimo , Crestani Alessandro , Togliardi Elena , Salvioni Roberto , Gianni Alessandro M. , Necchi Andrea
Published: February 2017

376

Background: Patients (pts) with germ cell tumors (GCT) who fail to be cured following multiple chemotherapy (CT) courses (± high-dose CT) have an extremely poor prognosis and long-term remissions are anecdotal. Pazopanib (PZP) is a potent and selective, orally available, TKI of VEGFR1, 2, and 3, PDGFRα, PDGFRβ, and cKit. Here we report the initial results of the ongoing open-label, single-group, phase II study which is sponsored by INT Milano (ClinicalTrials.gov NCT01743482). Methods: Pts with refractory GCT received pazopanib 800 mg/day orally until disease progression or evidence of unacceptable toxicity/side effects. Eligibility requirements included failure of at least two platinum-based CT, including high-dose CT. All pts underwent measurement of serum tumor markers (STM), a computed tomography and a FDG-PET after one month of treatment and q2 months thereafter. Results: From May 2013 to July 2013, five pts were enrolled, three in fourth, and two in fifth-line. Median age was 39 (IQR: 33 to 48). Three out of five had failed high-dose chemotherapy (HDCT), two had an extragonadal primary, all pts had at least one elevated STM at baseline, the sole parameter in one patient, two had liver metastases, four pts had a retroperitoneal relapse. Four had elevation of alfafetoprotein (AFP), one of human choriogonadotropin (HCG). Four were nonseminomas, one a pure seminoma. After the first month of treatment, four out of five pts had a decrease in marker levels, one patient had disease progression (PD). Two of the responding pts had a necrotic evolution of disease at computed tomography corresponding to a RECIST and metabolic (PET/CT) progression, two had a stable disease. Two-month follow up is available for three out of four responders: one interrupted PZP for toxicity and had a marker PD, another an increase to baseline levels and the last one a further reduction (pure seminoma, one out of five confirmed response at two months). There were two cases of hepatic toxicities (one G2 and one G3-4 with dose interruption). Conclusions: PZP is endowed with preliminary activity in extensively pretreated patients with GCT. The unique availability of STM in interpreting densitometric and metabolic response might provide insights into response assessment of solid tumors under antiangiogenic therapy. Clinical trial information: NCT01743482.
Risk of renal cell cancer in people immunodepressed after solid organ transplant: Results from an Italian multicenter cohort study.
Authors: Piselli Pierluca , Busnach Ghil , Citterio Franco , Burra Patrizia , Ettorre Giuseppe Maria , Segoloni Giuseppe Paolo , Messa Piergiorgio , Sandrini Silvio , Rigotti Paolo , Scolari Maria Piera , Piredda Gian Benedetto , Donati Donato , Maresca Maria Cristina , Tisone Giuseppe , Sparacino Vito , Vizzini Giovanni Battista , Cimaglia Claudia , Fratino Lucia , Serraino Diego , Grandaliano Giuseppe ,   The Immunosuppression and Cancer Study Group
Published: February 2017

422

Background: The etiology of renal cell cancer (RCC) is poorly understood, and data from immunosuppressed population may help to highlights risk factors unknown in the immune competent population. To assess incidence and risk factors for renal cell cancer (RCC) after kidney and liver transplant (KT and LT, respectively), we carried out a cohort investigation in 24 Italian transplant centers. Methods: This study is part of an ongoing cohort investigation conducted in 24 transplant centers in all of Italy. Two cohorts have been implemented, including 7,217 KT recipients (64.2% men) and 2,770 LT recipients (74.7% men) transplanted between 1997 and 2009—and followed-up until 2010. Person years (PY) at risk of cancer were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis (for KT) or to study closure. The number of observed cancers was compared to that expected in the general population through standardized incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed through Poisson regression. Results: Overall, 581 cancers were diagnosed during 61,817 PYs of follow-up, with Kaposi’s sarcoma, non-Hodgkin lymphoma, lung, RCC, and prostate as the most common types. Thirty-eight cases of RCC were diagnosed (36 in KT and 2 in LT). As compared to the general population, the risk of RCC was 4.9-fold significantly higher in KT recipients than expected (95% CI: 3.4-6.8). The increased risk was restricted to the native kidney (31 native kidney OR=4.2, 95% CI:2.9-6.0), and no risk elevation was found in LT recipients (SIR=0.5 95% CI: 0.1-1.9). Use of mTOR inhibitors seemed to exert a 40% reduced risk (IRR=0.6, 95% CI: 0.2–1.4) of RCC, but the difference was not statistically significant. Conclusions: Our study findings confirmed, in Italy, the increased risks for RCC following KT, and they also suggested a possible protective effect of mTORi. The magnitude of the excess risk documented in this cohort study was higher than reported for potential risk factors described in immune competent people—or in people under dialysis—thus suggesting a role for the immune system in the etiology of RCC.
The role of obesity in the incidence of lymphatic spread, disease-free, and overall survival: Data from the ARISER clinical trial.
Authors: Chamie Karim , Kloepfer Pia , Fall Barbara , Said Jonathan W. , Störkel Stephan , Bevan Paul , Belldegrun Arie S. , Pantuck Allan J. ,   ASCO
Published: February 2017

435

Background: The role of obesity and the incidence of high-risk clear cell renal cell carcinoma (ccRCC) are poorly understood. We examined the association of obesity with lymphatic spread and survival using data from an international Phase III clinical trial testing the efficacy of adjuvant treatment with cG250 antibody in subjects with non-metastatic (ccRCC) at high risk for recurrence. Methods: We reviewed the clinical and pathologic records of 864 patients across three continents and 14 countries that were enrolled in a prospective, double blind, placebo controlled study of adjuvant cG250 Ab treatment for high-risk ccRCC. Clinical features analyzed included age, gender, race, body mass index (BMI), and performance status. A single pathologist centrally reviewed the specimens for TNM stage and nuclear grade. BMI was stratified into normal (<25 kg/m2), overweight (25.0–29.9 kg/m2), obese (30.0–34.9 kg/m2), and morbidly obese (≥35 kg/m2). We examined the association between BMI, disease severity, and survival using logistic and Cox regression analyses, respectively. Results: Mean BMI was 28.2 kg/m2. The vast majority of our cohort was overweight (43%) and an additional 29% were obese (or morbidly obese). The incidence of lymphatic spread decreased with rising BMI: normal was 11%; overweight was 8%; obese was 5%; and morbidly obese was 2%. Obesity was associated with improved disease-free and overall survival, log rank=0.01 and <0.01, respectively. When compared with those who were normal in weight, subjects who were obese (HR 0.50, p<0.01) and morbidly obese (HR 0.22, p<0.01) had significantly improved overall survival. A trend towards improved disease-free survival was found among subjects who were obese (HR 0.77, p=0.10) and morbidly obese (HR 0.69, p=0.09). Conclusions: While we cannot speak to the association between obesity and ccRCC, our study demonstrates that in a cohort of nephrectomized patients with high-risk disease, obesity is associated with a lower risk of lymphatic spread and improved overall survival.
Retrospective observational study of sunitinib administered on schedule 2/1 in patients with metastatic renal cell carcinoma (mRCC): The rainbow study.
Authors: Bracarda Sergio , Iacovelli Roberto , Rizzo Mimma , Rossi Marta , Galli Luca , Procopio Giuseppe , Longo Flavia , Santoni Matteo , Morelli Franco , di Lorenzo Giuseppe , Porta Camillo , Camerini Andrea , Di Bella Sara , Martignetti Angelo , Gasparro Donatello , Sabbatini Roberto , Ceresoli Giovanni Luca , Mosca Alessandra , Santini Daniele , Boni Luca
Published: February 2017

471

Background: Sunitinib is a standard of care in first line mRCC; however, an increasing percentage of treatment-related adverse events are observed in the last 2 treatment weeks of the standard schedule 4/2 (4-weeks-on/2-weeks-off). In a multicenter, retrospective study, we evaluated the efficacy and safety of a modified 2/1 schedule (2-weeks-on/1-week-off), largely used in Italy based on a favorable initial experience. Methods: Data from all consecutive patients (pts) treated in 24 Italian centers with sunitinib on schedule 2/1 were analyzed according to the following groups: Group A, pts moved to schedule 2/1 because of treatment-related toxicities during initial therapy using schedule 4/2; Group B, pts treated ab initio with schedule 2/1, mainly because of poorer clinical conditions. A small group of pts treated with schedule 4/2 served as a control (Group C). Results: 276 consecutive pts treated from November 2005 to August 2013 were analyzed, including 249 treated with schedule 2/1 (Group A, n=208; Group B, n=41; respectively, median age 62 and 61 years; clear cell 94.7% and 87.8%; MSKCC good/intermediate/poor 47.1%/46.6%/6.3% and 36.5%/53.7%/9.8%; brain metastases 3.8% and 9.8%) and 27 pts in Group C (median age 59 years; clear cell 96.3%; MSKCC good/intermediate/poor 22.2%/70.4%/7.4%; no brain metastases). In Group A, the median treatment duration (TD) was 28.2 months (m) (with a median of 4.3 on the initial schedule 4/2 and 19.7 on the following schedule 2/1); median progression-free survival (PFS) was 38.6 m (95% CI, 24.0-58.6). In Group B (with less clear cell cases and more pts of intermediate risk or with brain metastases) median TD was 7.8 m and median PFS was 9.6 m (95% CI, 6.3-14.2). Median TD in Group C was 10.4 m. Maximum toxicity grade (≥3) and specific toxicities such as fatigue and hypertension were significantly reduced on schedule 2/1 in Group A compared with the initial schedule 4/2 (respectively, 8% vs 46% and 0% vs 10%, p < .001, and 2% vs 9%, p = .007). Conclusions: In our experience, sunitinib on a modified schedule 2/1 has an improved safety profile and increased efficacy compared with schedule 4/2. Prospective evaluation of this schedule is warranted.
Impact of obesity on outcomes after definitive dose escalated intensity modulated radiation therapy for localized prostate cancer.
Authors: Wang Lora S , Ruth Karen J. , Smaldone Marc C. , Kutikov Alexander , Sobczak Mark L. , Viterbo Rosalia , Horwitz Eric M.
Published: February 2017

50

Background: Multiple retrospective studies have investigated the association between body mass index (BMI) and biochemical failure (BF) after definitive external beam radiotherapy (EBRT) of localized prostate cancer (CaP) prior to the dose escalation era, with conflicting results. The purpose of this study is to determine whether increasing BMI is associated with CaP outcomes in patients treated with dose escalated radiotherapy. Methods: From 2000 to 2010, we identified 1,291 patients with localized (T1b-T4N0M0) CaP who were treated with definitive intensity modulated radiation therapy (IMRT). BMI was categorized using World Health Organization classification. Multivariable competing risk and Cox proportional hazards regression models were used to assess the risk of BF, distant metastasis (DM), cause-specific mortality (CSM) and overall mortality (OM). BF was defined as prostate-specific antigen (PSA) greater than or equal to nadir + 2 ng/mL. Covariates included age, androgen deprivation therapy (ADT), pre-treatment PSA (iPSA), Gleason score, and T stage. For OM, self-reported history of diabetes, heart disease, and hypertension were included. Results: Of the 1,291 patients identified, there were 20% normal (BMI<25 kg/m2), 47% overweight (BMI 25-29.9), 23% obese class I (BMI 30-34.9), 6% obese class II (BMI 35-39.9), and 4% obese class III (BMI >40). Median follow-up was 43.7 months (range 1.1-127) with median age of 68 (range 36 to 88). Median dose was 78 Gy (range 76-80) and 33% of patients received ADT. Increasing BMI was inversely associated with age (p<0.0001) and iPSA (p=0.047). There were 128 BF, 51 DM, 15 CSM, and 119 OM. Risk of BF, CSM, and OM were increased for obese class II and III compared to normal (all p<0.05). On multivariable analysis, for BF, HR was 2.1(p=0.057) for obese class II and 2.5 (p=0.043) for class III. For CSM, HR was 5.1 (p=0 .028) for class II and 5.15 (p=0.014) for class III. For OM, HR was 2.3 (p=0.022) for class II and 2.6(p=0.023) for class III. There was a trend toward increased DM for class III (p=0.057). Conclusions: For CaP patients receiving IMRT, those with higher levels of obesity may be at increased risk of BF and prostate cancer mortality, and should be considered for more aggressive treatment.
Treatment pattern and prognosis in Japanese patients with metastatic renal cell carcinoma (mRCC) with favorable or intermediate MSKCC risk factors in the era of molecular targeted therapy.
Authors: Shinohara Nobuo , Maruyama Satoru , Obara Wataru , Tatsugami Katsunori , Naito Sei , Kamba Tomomi , Naito Seiji ,   Japanese Collaboration Group
Published: February 2017

532

Background: We investigated the prognosis of Japanese mRCC patients with favorable or intermediate MSKCC risk factors in the era of molecular targeted therapy Methods: Data on patients who started systemic therapies including cytokine and molecular targeted therapies at 18 hospitals between 2008 and 2010 was analyzed. Of these, 269 patients classified as favorable or intermediate prognosis according to MSKCC risk classification were the subject of this analysis. The endpoints of the present study were progression-free survival (PFS) and overall survival (OS). Relationships between PFS or OS and clinical variables were assessed using the Cox-proportional hazard model. Results: The median OS of all 268 patients was 38 month, and 3-year OS rate was 51% (95%CI 45-58). Regarding the first-line therapy, IFN-alfa (IFN), sunitinib (SU), sorafenib (SO), and others were administered in 89 (33%), 104 (39%), 40 (15%), and 35 (13%). There were more patients without nephrectomy and with multiple organ metastases in patients received SU or SO compared to patients received IFN. Median PFS (mPFS) and 1-year PFS rate in patients who received IFN, SU, and SO were 5 months and 38%, 12 months and 50%, and 11 months and 48% (p=0.556), respectively. Second-line therapy was performed in 69 patients of first IFN group (mPFS: 9 months), 67 of first SU group (mPFS: 7 months), and 24 of first SO group (mPFS: 3 months). Third-line therapy was performed in 47 patients of first IFN group (mPFS: 11months), 35 of first SU group (mPFS: 5 months) and 12 of first SO group (mPFS 3 months). Median OS in patients who received IFN, SU, and SO as first-line therapy were 45, 29 and 27 months (p=0.093), respectively. Multivariate analysis demonstrated that lower value of serum C-reactive protein and first IFN therapy were associated with more favorable OS (p<0.05). Conclusions: In Japanese mRCC patients with favorable or intermediate MSKCC risk factors, first IFN therapy would still be appropriate even in the era of molecular targeted therapy. Furthermore, more potent sequential strategy after first molecular targeted therapy should be established for the improvement of OS.
Results of a phase II trial of novel carbonic anhydrase IX radiotracer 18F-VM4-037 in renal cell carcinoma.
Authors: Metwalli Adam R. , Turkbey Baris , McKinney Yolanda , Weaver Juanita , Yaqub-Ogun Nana , Merino Maria , Lindenberg Maria Liza , Linehan W. Marston , Choyke Peter L.
Published: February 2017

LBA400

Background: Carbonic Anydrase IX (CAIX) has been identified as a potential marker for clear cell renal cell carcinoma (ccRCC). We report the results of a phase II clinical trial of a novel small molecule radiotracer that binds to CAIX in clinically localized kidney tumors or biopsy proven metastases. Methods: Between October 2012 and May 2013, patients with kidney tumors underwent imaging with the 18F-VM4-037 radiotracer within 4 weeks of biopsy or surgery for kidney tumors. Imaging characteristics with the radiotracer were collected. All H&E pathology was centrally reviewed by a single pathologist. Immunohistochemistry of the surgical specimens for CAIX and Carbonic Anhydrase XII (CAXII) was reviewed by two experienced pathologists. Primary objectives were to evaluate the biodistribution of the radiotracer within tumor and non-tumor tissues as well to assess the safety of the radiotracer in patients. Results: 12 patients were enrolled and 11 received radiotracer and images were obtained. All patients tolerated the radiotracer well with no significant adverse events. 10 of the 11 patients had histologically confirmed malignancy. 1 patient had a complex cyst with no tumor found at surgery. Two patients had extrarenal disease and 9 had tumors in the kidney only. 100% had ccRCC and 4/11 had germline VHL mutations. Mean SUV for the entire group as 5.44 in the index lesions; in patients with histologically confirmed ccRCC the mean SUV was 5.91. 12 samples were stained for CAIX and CAXII including a biopsy obtained from a lung metastasis in one patient. The concordance between pathologists for CAIX IHC was 75%, for CAXII was 67%. Of the CAIX IHC slides, 67% had 3+ staining, 25% had 2+ and one specimen did not demonstrate CAIX staining. Only one specimen demonstrated 3+ staining for CAXII; 2 specimens had no detectable staining for CAXII and the remainder stained 1-2+ for CAXII. Conclusions: The 18F-VM4-037 was well tolerated and demonstrated modest signal uptake in tumors within the kidney. Immunohistochemistry staining for CAIX and CAXII was robust in nearly all tumors making correlation with radiotracer signal difficult. Larger studies are needed to evaluate the diagnostic performance of this radiotracer. Clinical trial information: NCT01712685.
Reduction in late mortality among 5-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Armstrong Gregory T. , Yasui Yutaka , Chen Yan , Leisenring Wendy M. , Gibson Todd M. , Mertens Ann , Stovall Marilyn , Hudson Melissa M. , Oeffinger Kevin C. , Bhatia Smita , Krull Kevin R. , Nathan Paul C. , Neglia Joseph Philip , Green Daniel M. , Robison Leslie L.
Published: February 2017

LBA2

Background: Over the past four decades, treatment of many childhood cancers has been modified with the aim of achieving high survival rates while reducing the risk of life-threatening late-effects, and promoting risk-based follow-up care of survivors. Methods: Late mortality was evaluated in 34,033 5-year survivors (diagnosed < 21 years of age from 1970-1999, median follow-up 21 years, range 5-38) using cumulative incidence and Poisson regression models adjusted for demographic and disease factors to calculate relative risk (RR) and 95% confidence intervals (CI). Mortality due to non-recurrence/non-external (NR/NE) causes, which includes deaths that reflect late-effects of cancer therapy, was evaluated. Results: 1,622 (41%) of the 3,958 deaths were attributable to NR/NE causes, including 751 subsequent neoplasm (SN), 243 cardiac, and 136 pulmonary deaths. Changes in therapy by decade included reduced rates of: cranial radiotherapy (RT) for acute lymphoblastic leukemia (ALL, 86%, 54%, 22%), RT for Wilms tumor (WT, 77%, 54%, 49%) and RT for Hodgkin lymphoma (HL, 96%, 88%, 77%). Reductions in 15 year cumulative NR/NE mortality were observed across treatment eras for ALL (p < .001), HL (p = .005), and WT (p = .005). Cardiac deaths decreased in ALL (p = .002), HL (p = .06), and WT (p = .04), and SN deaths decreased in WT (p < .001). Year of diagnosis (adjusted for age, sex, diagnosis, follow-up time) was significantly associated with a reduced risk of all-cause mortality (RR = 0.85, CI 0.83-0.87), NR/NE death (RR = 0.87, CI 0.84-0.91), death from SN (RR = 0.84, CI 0.80-0.89), cardiac death (RR = 0.78, CI 0.69-0.87) and pulmonary death (RR = 0.79, CI 0.68-0.91). Conclusions: The CCSS cohort provides evidence that the strategy of modifying therapy to reduce the occurrence of late-effects, and promotion of early detection, is successfully translating into a significant reduction in observed late mortality. [Table: see text]
Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study.
Authors: Chanan-Khan Asher Alban Akmal , Cramer Paula , Demirkan Fatih , Fraser Graeme , Silva Rodrigo Santucci , Pylypenko Halyna , Grosicki Sebastian , Janssens Ann , Pristupa Alexander , Mayer Jiri , Dilhuydy Marie-Sarah , Loscertales Javier , Bartlett Nancy L. , Avigdor Abraham , Rule Simon , Sun Steven , Mahler Michelle , Salman Mariya , Howes Angela J. , Hallek Michael J.
Published: February 2017

LBA7005

Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. Clinical trial information: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.
Preferences in educational topics of interest to women with triple-negative breast cancer: The role of age, race/ethnicity, and stage at diagnosis in topic selection.
Authors: Swiger Kathleen Dickerson , Guglielmino Janine E. , Labban Jeffrey D. , Rugo Hope S. , Anders Carey K. , Nelson Hillary C.M. , Hanson Arin Ahlum , Dinerman Hayley , Henry Catherine Creme
Published: February 2017

100

Background: Women diagnosed with triple-negative breast cancer (TNBC) responded to an online 80-question survey to identify their educational needs. They self-reported breast cancer subtype, demographics, and level of interest in 35 educational topics. Methods: This analysis examined whether demographic factors of women with TNBC diagnosed after 2006 (n = 611) were associated with their topic interest. Interest ratings were collapsed into “Not Interested” and “Interested or Very Interested.” Measures of association between interest in the top 10 TNBC topics and demographic factors were calculated using Phi coefficients (white/non-white) and point biserial correlations (age, cancer stage at diagnosis). False discovery rate adjustments were applied to the significance threshold to account for multiple comparisons. Results: Significant levels of association between personal factors and topic interest were observed for age; younger women were more likely to be interested in breast reconstruction (rpb= -19), parenting issues (rpb= -.36), and fertility preservation (rpb= -.33). Marginally significant associations were observed for race/ethnicity and cancer staging: non-white women were more likely to be interested in fertility preservation (rpb= -.12), and women diagnosed initially at higher stages of disease were more likely to be interested in parenting issues (rpb= .11). Conclusions: Age, race/ethnicity, and stage can influence education preferences of women with TNBC. These data point to the importance of understanding the interaction of children and cancer stage in women with triple-negative breast cancer. TNBC is proportionately more common in younger and non-white women; therefore, developing targeted interventions to address these factors could maximize healthcare team interactions, and enhance quality of life.
Efficacy of screening and treatment of breast cancer patients reporting high level of distress.
Authors: West Ryan , Thomas John W , Smith Elaine , Dhillon Navneet , Pabbathi Haritha , McKnight John Edward , Johnson Anita , Alvarez Ricardo H.
Published: February 2017

101

Background: Cancer patients (pts) are burdened by symptoms related to the disease itself or to the toxicities of treatment. The ASCO clinical oncology guideline adaptation recommends all health care providers routinely screen for the presence of emotional distress and specifically symptoms of anxiety from the point of diagnosis onward [Andersen BL, 2014].At Cancer Treatment Centers of America (CTCA) we perform screening assessments using a Symptom Inventory Tool (SIT) composed of 27 questions. Pts with moderate and severe levels of anxiety are evaluated by the Integrative Resource Assessment Program (IRAP) and subsequently referred to integrative oncology consultation. Methods: The SIT is an assessment tool that captures pts’ perceived symptom burden for real-time clinical intervention, taken at the point of no intervention (baseline) and every 21 days or greater. The SIT is comprised of 27 questions utilizing the M.D. Anderson Symptom Inventory tool (MDASI) and validated assessment instrument with 8 questions and a free text box added by CTCA. Symptoms were rated “at the worst” on an 11-point numeric scale ranging from 0 (“no present”) to 10 (“as bad as you can imagine”) in the previous 24 hours. Results: Between 9/1/2014 and 2/27/2015, 842 pts with multiple types of cancer were screened for distress and 435 (51.6%) scored 5 or greater, of which 212 completed a second screening assessment.58 breast cancer pts provided SIT distress scores at baseline and then again at least 23 days after the initial assessment. The average reduction in the distress scores for breast cancer patients was 2 (1st SIT mean = 6.2, 2ndSIT mean = 4.2) with 40 pts (69%) reporting a decrease, 7 pts (12%) having no change, and 11 pts (19%) reporting an increase in distress. The 4 interventions most frequently referred and completed by the pts were mind body therapy (100%), rehabilitation (66%), acupuncture (50%), and massage therapy (45%). Conclusions: Distress is a relevant symptom reported by cancer pts. This study demonstrates that early intervention in breast cancer pts using integrative oncology approaches will reduce the distress in 69% of cases.