bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of somatic mutation profiles from cell free DNA (cfDNA) versus tissue in metastatic urothelial carcinoma (mUC).
Authors: Cheng Michael L. , Shady Maha , Cipolla Catharine Kline , Funt Samuel , Arcila Maria E. , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Bajorin Dean F. , Berger Michael F. , Tsui Dana , Solit David B. , Iyer Gopa
Published: September 2018

4533

Background: Next-generation sequencing (NGS) of cfDNA is an emerging non-invasive strategy to define tumor mutation profiles that counters spatial and temporal limitations of sequencing single tissue specimens. We examined the feasibility of NGS of cfDNA in mUC and compared mutation profiles from cfDNA to results of tissue NGS previously performed in the clinical setting. Methods: Plasma cfDNA was collected in mUC pts and analyzed using a capture-based NGS assay (MSK-IMPACT) targeting 341-468 genes. NGS profiles from cfDNA and archival tumor tissue (using the same assay) were analyzed in parallel with an established bioinformatics pipeline to identify somatic variants. Results: In 26 pts, NGS analysis of cfDNA detected ≥1 somatic mutations (range 1-21) in 69% (18/26). For 15 pts, NGS data was available from archival tissue (11 primary tumors, 3 metastases, and matched primary/metastatic tissue in 1 case). The interval between cfDNA and tissue collection ranged from 35 days to > 4 yrs. 73% (11/15) of pts received intervening treatment, including 47% (7/15) with chemotherapy, 67% (10/15) with immunotherapy, and 40% (6/15) with both. In 40% (6/15), cfDNA harbored alterations not found in archival tumor tissue. In 73% (11/15), some mutations within archival tissue were not detected in cfDNA, including hotspot HER2 S310F and FGFR3 S249C mutations. Tumor and cfDNA mutation profiles were identical in 20% (3/15), with the tumor/cfDNA interval in this group ranging from 35 days to < 1.5 yrs. Somatic alterations including hotspot ERCC2 P463A and PIK3CA E545K mutations were detected in cfDNA from 3 pts where archival tumor tissue NGS failed. Thus, cfDNA identified new mutations in 50% (9/18) of pts for whom cfDNA identified somatic mutations and tissue NGS was previously attempted. Conclusions: NGS of cfDNA from mUC pts is feasible and successfully detected actionable alterations when archival tumor sequencing failed. The differences between tumor and cfDNA mutation profiles in many pts may reflect tumor evolution or intratumor heterogeneity. Mutation profiles in mUC may be incompletely assessed with NGS of archival tissue, and further investigation of plasma cfDNA for genomic profiling is warranted.
Efficacy of epirubicin-paclitaxel (EPI-TAX) prior to high-dose chemotherapy (HDCT) in germ cell tumors (GCTs): A 17-year experience.
Authors: Lotz Jean-Pierre , Soares Daniele Grazziotin , Culine Stephane , Laverdant Benjamin , Kieffer Anne , Dabi Yohann , Gligorov Joseph , Selle Frederic
Published: September 2018

4557

Background: GCTs patients (pts) relapsing after conventional-dose salvage chemotherapy (CDCT) are candidates to receive HDCT with hematopoietic stem cell (SC) support. We have previously reported (Ann Oncol 2014; 25:1775-82) that non-refractory pts can benefit from HDCT. We here analyzed the efficacy of the induction regimen EPI-TAX. Methods: All male GCTs pts treated by EPI-TAX between 1998 and 2015 were identified from clinical records at Tenon Hospital. Primary aim was response rate after EPI-TAX. Secondary aims were efficacy of SC harvest, Beyer score, toxicities and overall survival (OS) after HDCT. Kaplan-Meier methods were used for analysis. Results: Of the 170 pts treated (EPI 100 mg/m2, TAX 250 mg/m2, days 1-15), 142 (83.5%) had received > 2 previous lines of CDCT. 79 (46.5%) had disease progression at the time of treatment and 44 were absolutely refractory to cisplatin. The other pts were in remission (65) or had stable disease (SD, 26). Most of pts (75.3%) had Beyer score > 1. Following EPI-TAX, favorable responses were achieved in 140 pts (82.4%,CI95% 79.8-85.0; 21 complete responses, 68 partial responses and 51 SD). EPI-TAX was able to control disease in 56 (70.9%, CI95% 61.0-80.8) out of 79 pts who were in progression. Beyer score after EPI-TAX resulted 0 in 70.6% of pts. Successful harvested of SC was achieved in 146 (85.8%, CI95% 80.5-91.1) pts. EPI-TAX was well tolerated with peripheral neuropathy as the main non-hematopoietic toxicity. Treatment discontinuation was needed in 3 (1.8%) pts and 2 (1.2%) related deaths were observed. Following EPI-TAX, 155 (91.2%) pts received HDCT. HDCT was given in consolidation, once progressive disease was controlled by EPI-TAX or for progressive pts. With a median follow-up of 31 months (0.5-223) the 2- and 10-years OS for the subgroup consolidation were 78.2% (95%CI 69.1-87.4) and 66.9% (95%CI 55.4-78.6). Disease control by EPI-TAX resulted in 55.8% (95%CI 42.4-69.2) and 38.2% (95%CI 24.9-51.4) 2- and 10-y OS compared to 14.6% (95%CI 0-33.2, logrank p = 0.006) 2-y OS for progressive pts. Conclusions: EPI-TAX is effective to collect SC and to control disease of pts who were in progression after CDCT allowing them to receive HDCT.
Applying radiomics to predict pathology of post chemotherapy retroperitoneal nodal masses in germ cell tumors (GCT).
Authors: Lewin Jeremy Howard , Dufort Paul , Halankar Jaydeep , O'Malley Martin , Jewett Michael A.S. , Hamilton Robert James , Gupta Abha A. , Lorenzo Armando J. , Traubici Jeffrey , Nayan Madhur , Leao Ricardo Romao Nazario , Warde Padraig Richard , Chung Peter W. M. , Anson-Cartwright Lynn , Sweet Joan , Hansen Aaron Richard , Metser Ur , Bedard Philippe L.
Published: September 2018

4559

Background: After chemotherapy, > 50% of patients (pts) with metastatic testicular GCT who undergo retroperitoneal lymph node dissection (RPNLD) for residual masses are found to have fibrosis (F) alone on pathological examination. To minimize overtreatment, better prediction algorithms are needed to identify pts with F who can avoid RPLND. Radiomics uses image processing techniques to extract quantitative textures/features from tumor regions of interest (ROI) to train a classifier that predicts pathological findings. We hypothesized that radiomics may identify pts with a high predicted likelihood of F who may avoid RPLND. Methods: Pts with GCT who had an RPLND for nodal masses > 1cm after first line platinum chemotherapy were included. Preoperative contrast enhanced axial CT images of retroperitoneal ROI were manually contoured. 153 radiomics features trained a radial basis function support vector machine classifier to discriminate between viable GCT /Mature Teratoma (T) vs F. Nested ten-fold cross-validation protocol was employed to determine classifier accuracy. Clinical variables and restricted size criteria were used to optimize the classifier. Results: A total of 82 pts with 102 ROI were analyzed (GCT: 21; T: 41; F: 40). The discriminative accuracy of radiomics to identify GCT/T vs F was 72%(±2.2)(AUC: 0.74 (±0.028); positive predictive value: 67% (48-92%); negative predictive value: 74% (62-84%)(p = 0.001)). No major predictive differences were identified when data was restricted by varying maximal axial diameters (AUC range: 0.58(±0.05) - 0.74(±0.03)). Prediction algorithm using clinical variables alone identified an AUC of 0.71 (±0.15). When these variables were added to the radiomic signature, the best performing classifier was identified when axial tumors were limited to diameter < 2cm (accuracy: 88.2 (±4.4); AUC: 0.80 (±0.05)(p = 0.02)). Conclusions: A predictive radiomics algorithm had an overall discriminative accuracy of 72% that improved to 88% when combined with clinical details. Further independent validation is required to assess whether radiomics, in conjunction with standard clinical predictors, may allow pts with a high predicted likelihood of F to avoid RPLND.
Microvessel density as a prognostic marker in high-risk renal cell carcinoma.
Authors: Weiss Sarah A. , Puligandla Maneka , Jilaveanu Lucia , Haas Naomi B. , Wang Xin Victoria , Zito Christopher , Boeke Marta , Neumeister Veronique , Manola Judith , DiPaola Robert S. , Kluger Harriet M.
Published: September 2018

4565

Background: Increased vascularity is a hallmark of renal cell carcinomas (RCC), particularly clear cell RCC. The vascular endothelial growth factor (VEGF) pathway, implicated in tumor angiogenesis, is dysregulated in RCC. The phase 3 trial ECOG-ACRIN E2805 enrolled 1,943 patients (pts) with resected high-risk RCC (pT1b high grade to pT4 any grade or N any). Pts were randomized to adjuvant sunitinib, sorafenib, or placebo. Our aim was to determine the prognostic and predictive role of microvessel density (MVD), VEGF receptors, and ligands in nephrectomy specimens. Methods: We obtainedpre-treatment primary RCC tissue from 822 pts and built tissue microarrays using 3 cores from each sample. Using quantitative immunofluorescence we measured tumor MVD (area of CD34-expressing cells) and intensity of the VEGF/VEGF-R family (VEGF-R1, R2, R3 and VEGF-A, B, C, D) in tumor cells. We tested for association with disease-free survival (DFS) and overall survival (OS) by the stratified log-rank test. Associations with treatment arm and clinicopathologic variables were determined. Results: High MVD (above the median) was associated with prolonged OS for the entire cohort (p = 0.021, HR 0.63) and for pts treated in the placebo group (p = 0.014). The association between high MVD and OS was weaker in patients treated with sunitinib or sorafenib (p = 0.060). High VEGFD expression overall was associated with shorter OS (p = 0.027) but not for placebo (p = 0.16). Yet high MVD was not associated with improved DFS (p = 1.00). High MVD correlated with above-median age ( > 56) (p = 0.032), Fuhrman grade I/II (p < 0.001), clear cell histology (p < 0.001), and absence of necrosis (p < 0.001) but not with gender, sarcomatoid features, lymphovascular invasion, or tumor size. In multivariable analysis, MVD remained independently associated with improved OS for the entire cohort (p = 0.013). Conclusions: High MVD in nephrectomy specimens of high-risk RCC pts is associated with improved OS, regardless of treatment arm. MVD is thus an independent prognostic, rather than predictive, biomarker. Further studies should assess whether incorporating MVD into clinical models will predict outcome in resected high-risk RCC pts and if MVD can be used for pt selection for adjuvant therapy.
Clinical outcomes by nephrectomy status in METEOR, a randomized phase 3 trial of cabozantinib (cabo) vs everolimus (eve) in patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Tannir Nizar M. , Powles Thomas , Escudier Bernard J. , Donskov Frede , Grünwald Viktor , Sternberg Cora N. , Schmidinger Manuela , Schoffski Patrick , Szczylik Cezary , Peltola Katriina Johanna , Nosov Dmitry , Melichar Bohuslav , Clary Douglas O. , Scheffold Christian , Motzer Robert J. , Choueiri Toni K.
Published: September 2018

4570

Background: Most pts with advanced RCC undergo nephrectomy (Nx) as curative or palliative therapy. In a retrospective analysis of pts treated with targeted therapy, pts who were older and had more comorbidities and higher tumor grade were less likely to have had Nx. Pts without Nx had shorter overall survival (OS) than pts with Nx (Hanna, J Clin Oncol 2016). Here we report outcomes for cabo vs eve in pts with advanced RCC with or without prior Nx in the phase 3 METEOR trial (NCT01865747). Methods: 658 pts with clear cell RCC and ≥1 prior VEGFR TKI were randomized 1:1 to receive cabo at 60 mg qd or eve at 10 mg qd. Stratification was by MSKCC risk group and number of prior VEGFR TKIs. Endpoints included progression-free survival (PFS), OS, and objective response rate (ORR). Results: 85% of enrolled pts had prior Nx of which 7% were partial; 15% had no prior nephrectomy (NoNx). Baseline characteristics, including Karnofsky performance status (KPS), MSKCC risk group, time from diagnosis to randomization, and median sum of diameters (SoD) for tumor target lesions, were less favorable for the NoNx subgroup (Table). Improved PFS and OS with cabo vs eve were observed regardless of Nx status. For the Nx subgroup, the hazard ratio (HR) was 0.51 (95% CI 0.41-0.64) for PFS and 0.66 (95% CI 0.52-0.84) for OS; for the NoNx subgroup, the HR was 0.51 (95% CI 0.30-0.86) for PFS and 0.75 (95% CI 0.44-1.27) for OS. Median OS was longer in the Nx subgroup for both treatment arms (Table). ORR per independent radiology committee (IRC) for cabo vs eve was 17% vs 4% for Nx and 21% vs 2% for NoNx. Grade 3 or 4 adverse events for both subgroups were generally consistent with the safety profiles of cabo and eve in the overall population. Conclusions: Cabo improved PFS, ORR, and OS compared with eve in pts with advanced RCC irrespective of nephrectomy status. Clinical trial information: NCT01865747. [Table: see text]
Checkpoint inhibitors in metastatic renal cell carcinoma patients including elderly subgroups: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Yip Steven , Wells Connor , Moreira Raphael Brandao , Wong Alex , Srinivas Sandy , Beuselinck Benoit , Porta Camillo , Sim Hao-Wen , Ernst D. Scott , Rini Brian I. , Yuasa Takeshi , Basappa Naveen S. , Kanesvaran Ravindran , Wood Lori , Canil Christina M. , Kapoor Anil , Fu Simon Yuen Fai , Choueiri Toni K. , Heng Daniel Yick Chin
Published: September 2018

4580

Background: Immuno-oncology (IO) checkpoint inhibitor treatment outcomes are poorly characterized in the real world metastatic renal cell cancer (mRCC) patient population, including geriatric patients. Methods: Using the IMDC database, a retrospective analysis was performed on mRCC patients treated with IO, as listed below. Patients received one or more lines of IO therapy, with or without a targeted agent. Duration of treatment (DOT) and overall response rates (ORR) were calculated. Cox regression analysis was performed to examine the association between age as a continuous variable and DOT. Results: 312 mRCC patients treated with IO were included. In patients who were evaluable, ORR to IO therapy was 29% (32% first-, 22% second-, 33% third-, and 32% fourth-line treatment (Tx)). Patients treated with second-line IO therapy were divided into favorable, intermediate, and poor risk using IMDC criteria; the corresponding median DOT rates were not reached (NR), 8.6 mo, and 1.9 mo, respectively (p<0.0001). Based upon age, hazard ratios were calculated in the first- through fourth-line therapy setting, ranging from 1.03 to 0.97. Conclusions: The ORR to IO appears to remain consistent, regardless of line of therapy. In the second-line, IMDC criteria appear to appropriately stratify patients into favorable, intermediate, and poor risk groups for DOT. Premature OS data will be updated. In contrast to clinical trial data, longer DOT is observed in real world practice. Age may not be a factor influencing DOT. [Table: see text]
Incidence of T3a upstaging and survival after partial nephrectomy: Size-stratified rates and implications for prognosis.
Authors: Srivastava Arnav , Patel Hiten , Kates Max , Schwen Zeyad , Joice Gregory , Semerjian Alice , Pierorazio Phillip M. , Gorin Michael A. , Allaf Mohamad
Published: September 2018

4588

Background: The use of partial nephrectomy (PN) to treat renal cell carcinoma has grown in the past decade, with expansion to larger tumors. Performing PN for larger tumors may increase the number of patients up-staged to pT3a after surgery, who may have underwent radical nephrectomy (RN), if known preoperatively. We aimed to estimate the proportion of patients up-staged to T3a disease after PN, stratified by size. We also compared size-stratified survival of up-staged pT3a patients to those with T1a, T1b, or T2 disease. Methods: From 1998 – 2013, we identified patients undergoing PN or RN from the Surveillance Epidemiology and End Results registries. The proportion of patients receiving PN found to have pT3a disease was quantified by size. Cox proportional hazards models compared cancer-specific (CSS) and overall survival (OS) for PN patients with pT1a, pT1b, and pT2 disease to size-stratified pT3a patients. Also, we compared PN patients with pT3a disease to RN patients with pT3a disease. Results: From the 28,854 patients undergoing PN, the estimated proportion up-staged to pT3a increased along with tumor size: 4.2% for T1a, 9.5% for T1b, and 19.5% for T2. Among those receiving PN, survival analysis showed worse CSS for up-staged pT3a patients versus stratified pT1a (HR = 1.87, p = 0.02), pT1b (HR = 1.91, p = 0.01), and pT2 (HR = 2.33, p = 0.01) patients. When assessing OS, only in tumors < 4cm did the pT3a cohort demonstrate worse OS (HR = 1.25, p = 0.04). Comparing PN and RN for pT3a disease, size-adjusted analysis revealed no difference in CSS or OS. Lastly, among pT3a patients undergoing PN, patients with larger tumors, measuring 4 – 7cm (OS: HR = 1.44, p = 0.04) or 7 – 16cm (OS: HR = 2.64, p < 0.01), had worse survival than those with tumors < 4cm. Conclusions: A greater proportion of patients experience T3a up-staging after PN with increasing initial T stage. Up-staged pT3a patients have worse CSS after PN compared to those with similarly sized localized tumors. Also, pT3a patients after PN showed similar survival to pT3a patients after RN. However, pT3a patients undergoing PN had worse survival with increasing tumor size, reinforcing the need for improvements in identifying patients at risk of up-staging.
A randomized phase II cross-over study of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Chi Kim N. , Annala Matti , Sunderland Katherine , Khalaf Daniel , Finch Daygen , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Beja Kevin , Vandekerkhove Gillian , Gleave Martin , Wyatt Alexander William
Published: September 2018

5002

Background: ABI and ENZ are indicated as 1st line therapy for mCRPC but have not been directly compared. Optimal sequencing of these agents has not been prospectively evaluated and predictive biomarkers are lacking. Methods: Multicenter, phase 2 study randomizing treatment-naïve mCRPC pts to ABI vs ENZ, with cross over at PSA progression. Primary endpoints: response and time to PSA progression (TTPP, PCWG3 criteria) after 2nd line therapy. Reported here are secondary endpoints: PSA ≥50% decline (PSA50) from baseline, TTPP with 1stline therapy, and correlation with deep targeted sequencing of 73 mCRPC genes in circulating tumor DNA (ctDNA). Results: Accrual completed October 2016 with 202 pts randomized (ABI:ENZ = 101:101). Median follow-up 12.8 months. Baseline characteristics were similar between arms: median for age was 75 years (range 49-94), PSA 36.1 (1.7-2817), HGB 130 (89-165), ALK PHOS 105 (31-6600), LDH 207 (77-3098). ECOG PS was 0-1 in 83%, presence of metastases in bone/liver/lung in 83%/6%/10%. With 1stline therapy for ABI vs ENZ, PSA50 at 12 weeks was 53% vs 73% (P = 0.004), no PSA decline occurred in 21% vs 15% (P = 0.243), and median TTPP was 7.4 vs 8.0 months (HR = 0.88, 95% CI 0.61, 1.27). Baseline ctDNA fraction was >2% in 60% of patients, and associated with worse TTPP (HR 1.80, P=0.005). Baseline pathogenic ctDNA alterations in AR, TP53, RB1, and DNA repair (BRCA2, ATM) genes were associated with a shorter TTPP (univariate analysis: TABLE). On multivariate analysis including clinical factors, TP53 and BRCA2/ATM alterations remained significant (HR = 2.54 (95%CI 1.55-4.19) and HR = 2.68 (1.58-4.54)). Pts with a PSA increase as best response were enriched for alterations in DNA repair (P <0.001), TP53 (P = 0.005), RB1 (P = 0.04), and (in 1 pt) a genomically truncated AR. Conclusions: There was a difference in PSA response for 1stline ABI vs ENZ, but no difference for TTPP. Baseline pathogenic ctDNA alterations, particularly in TP53 and BRCA2, identify pts with poor outcomes. Clinical trial information: NCT02125357. [Table: see text]
Whole exome sequencing (WES) of circulating tumor DNA (ctDNA) in patients with neuroendocrine prostate cancer (NEPC) informs tumor heterogeneity.
Authors: Beltran Himisha , Romanel Alessandro , Casiraghi Nicola , Sigouros Michael , Benelli Matteo , Xiang Jenny , Demichelis Francesca
Published: September 2018

5011

Background: We recently identified mechanisms underlying the clonal evolution of castration-resistant prostate adenocarcinoma (CRPC-Adeno) to a neuroendocrine resistance phenotype (Beltran et al, Nat Med 2016). We aimed to develop a non-invasive approach to identify patients that are developing NEPC. Methods: We performed whole exome sequencing of matched ctDNA, germline DNA, and metastatic biopsies from patients with CRPC-Adeno and NEPC. After applying ad hoc partial duplication filtering, we used FACETS and extended CLONET to calculate the fraction of tumor DNA and clonality of genomic lesions. Results: 64 CRPC patients were prospectively enrolled. The spectrum of alterations captured by WES of ctDNA was consistent with those commonly observed in CRPC validating the feasibility of the approach. The similarity of copy number alterations between tumor tissue and ctDNA was higher in NEPC compared to CRPC-Adeno (p = 0.0001) suggesting less heterogeneity in NEPC. There was enrichment of RB1 and TP53 loss in NEPC ctDNA and ARgains in CRPC-Adeno. The overall fraction of mutations shared by ctDNA and tumoral tissue was ~80%. We compared three different tumor biopsy time-points of patient PM161—CRPC-Adeno (lymph node), CRPC-Adeno (bone), NEPC (liver). Unexpectedly the baseline ctDNA profile (at time of CRPC-Adeno) displayed genomic features most similar to the NEPC liver biopsy. These data suggest that NEPC alterations are detectable in the circulation potentially prior to the development of NEPC clinical features. We compared the ctDNA of another patient PM0 with 6 sites of NEPC metastases obtained 6 days later at autopsy; the relative contribution of tumor alterations in ctDNA was highest for the liver metastasis (similarity 0.59) versus other sites suggesting differential contribution of metastatic sites in the circulation, with implications for the interpretation of single site clinical biopsies. Conclusions: This is the first study to show that WES of ctDNA is feasible in CRPC and can help elucidate intra-patient heterogeneity and identify the spectrum and frequency of NEPC genomic changes. ctDNA may improve the detection of patients transforming towards NEPC.
Impact of timing of administration of bone supportive therapy on pain palliation from radium-223.
Authors: Yap Kelly Khai Li , Wong William , Ji Lingyun , Groshen Susan G. , Quinn David I. , Pinski Jacek K. , Bryce Alan Haruo , Dorff Tanya B.
Published: September 2018

5023

Background: Skeletal-related events (SREs) drive morbidity in patients with metastatic castration-resistant prostate cancer (mCRPC). In the ALSYMPCA study, Radium-223 (Ra223) was found to palliate pain in addition to prolonging survival and reducing SREs. Earlier onset of pain relief was noted when zoledronic acid (ZA) was administered within 24-48 hours of samarium; we evaluated whether the timing of bone supportive therapy (BST) affected pain palliation fromRa223. Methods: We identified patients who received Ra223 at University of Southern California or Mayo Clinic Arizona. Data extracted: Ra223 administration dates, pain scores, pain medications, ZA or denosumab administration dates, alkaline phosphatase (ALP) levels, prostate specific antigen (PSA) levels, and concurrent prostate cancer therapy. Patients were evaluable for pain response if they had at least 2 pain scores documented before and after Ra223 with pain medication use data. Pain response was defined as > 2 point decrease in pain on a 10 point scale; flare was defined as > 2 point increase followed by return to baseline or lower. Results: Of 65 patients, 20 had baseline pain score > 0 and 34 were evaluable. Median #doses Ra223 was 5 (range 2-6). 18 patients received concurrent abiraterone (abi) or enzalutamide (enza), 16 did not. Pain response occurred in 6/6 (100%) patients who received BST within 1 month prior to first Ra223 dose and 4/8 (50%) patients who did not receive BST. Pain flare occurred in 6/21 patients (29%) without BST and 2/13 (15%) with BST. 6/10 (60%) patients with pain response had ALP decline but there was no consistent pattern of ALP changes in patients with flare. 8/8 patients with pain response had no PSA decline (6 increased, 2 stable). 6/12 (50%) and 2/22 (9%) patients on abi/enza had pain response and flare respectively, and 4/8 (50%) and 6/19 (32%) patients without concurrent abi/enza had response/flare. Conclusions: BST within 1 month prior to first Ra223 may be associated with increased likelihood of pain palliation and may prevent pain flare. PSA/ALP changes do not predict pain response. Concurrent use of abi/enza does not increase the likelihood of pain response and may decrease the likelihood of flare.
Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for Neuroendocrine Prostate Cancer (NEPC).
Authors: Puca Loredana , Sailer Verena , Gayvert Kaitlyn , Isse Kumiko , Sigouros Michael , Nanus David M. , Tagawa Scott T. , Mosquera Juan Miguel , Saunders Laura , Beltran Himisha
Published: September 2018

5029

Background: TheNotch ligand Delta like ligand 3 (DLL3) is aberrantly expressed on the cell surface of small cell lung cancer (SCLC), and the DLL3-antibody drug conjugate, Rova-T, has shown promise for patients with SCLC (Rudin et al, Lancet Onc 2017). NEPC is a late stage subtype of castration resistant prostate cancer with limited therapeutic options. Based on clinical and molecular similarities with SCLC, we investigated expression of DLL3 and the use of Rova-T in NEPC. Methods: We evaluated mRNA and/or protein expression of DLL3 in a cohort of 395 patients (535 samples) ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and NEPC and correlated with pathologic and genomic features. Prostate cancer cell lines and patient-derived organoids were treated with Rova-T (SC16LD6.5) in vitro and in vivo. Results: DLL3 was expressed at the mRNA and/or protein level in 0/143 BEN (0%), 4/266 PCA (1%), 8/76 CRPC (10%), 33/50 NEPC (66%). DLL3 IHC was of higher intensity in NEPC and co-localized with classical NE marker expression (SYP, CGA). DLL3 was amongst the most differentially expressed genes by RNA-seq in NEPC versus CRPC (p = < 0.0001, fold change = 71), correlated with ASCL1 expression (r = 0.88) and RB1 genomic loss (83%), and inversely with AR expression. Although treatment with the Notch inhibitor DAPT suppressed Notch target gene expression in NEPC, DAPT did not have significant effect on cellular proliferation. siRNA knockdown of DLL3 or DAPT did not alter AR signaling or NE markers. Rova-T (SC16LD6.5) was active in DLL3-positive NEPC cell lines with an IC50 of 580pM compared to the control IgG1LD6.5 (IC50 = 6.3nM), whereas CRPC lines were insensitive. Conclusions: DLL3 is a cell surface protein aberrantly expressed in the majority of NEPC and a subset of CRPC, and is not expressed in primary prostate cancer or benign tissues. The DLL3 antibody-drug conjugate Rova-T demonstrates preferential preclinical activity in NEPC compared to prostate adenocarcinoma. These data support further investigation of Rova-T as a potential therapeutic agent for NEPC. A phase I trial with dedicated NEPC arm is currently accruing patients (NCT02709889).
Circulating tumor cell subsets and macrophage polarization to predict efficacy of cabozantinib in advanced prostate cancer with visceral metastases.
Authors: Posadas Edwin M. , Chen Jie-Fu , Tripathi Manisha , Lu Yi-Tsung , Montes Alexander , Go Ann , Ureno Alexander , Cavassani Karen Angelica , Sievert Margarit , Rogatko Andre , Limvorasak Suwicha , Oppenheim Amy , Moldawer Nancy P. , Chung Leland WK , Bhowmick Neil , Tseng Hsian-Rong , Figlin Robert A.
Published: September 2018

5031

Background: The presence of VM in metastatic, castration-resistant prostate cancer (mCRPC) predicts poor survival. Cabozantinib (cabo) is a multi-kinase inhibitor that has clinical activity that did not improve survival in an unselected mCRPC population. Subgroup analyses suggested that the benefit may exist for patients (pts) with mCRPC-VM. The effect of cabo includes the tumor microenvironment, monocytes in particular, which in turn can alter tumor behavior. Methods: We conducted a single-arm study of cabo in men with mCRPC-VM. Pts received cabo 60 mg daily. Radiographs were used to assess response. Correlative blood samples were collected for the enumeration and characterization of circulating tumor cells using the NanoVelcro Assay and analysis of circulating monocytes by FACS. Results: A total of 17 pts enrolled with 16 evaluable for response. At 12 weeks, 19% experienced partial responses (PR), 44% stable disease (SD), and 38% progressive disease. The clinical benefit rate (PR+SD) at 12 weeks was 63%. Safety profile was consistent with previous reports. CTCs were detected in 80% of pts. NanoVelcro CTC counts showed reduction by week 8 in both PR+SD (88%) and PD (71%) groups with re-emergence at progression. Among pts with liver metastases, very-small-nuclear CTCs ( < 8.5 μm) were seen in 29% of pts with clinical benefit compared to 60% in non-benefiters. Analysis of monocyte polarization after initiation of therapy showed that reduction of M1 polarization was associated with improvement in bone pain and/or bone scan. Conclusions: In heavily-pretreated mCRPC-VM, cabo provided clinical benefit with acceptable toxicity. Circulating biomarkers related to both tumor and microenvironment may be useful in identifying patients who benefit from this type of therapeutic approach. Clinical trial information: NCT01834651.
Avelumab in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fakhrejahani Farhad , Madan Ravi Amrit , Dahut William L. , Bilusic Marijo , Karzai Fatima , Cordes Lisa M , Strauss Julius , Schlom Jeffrey , Gulley James L.
Published: September 2018

5037

Background: Despite recent progress, mCRPC remains a lethal disease. While programmed cell death 1 (PD-1) and PD-1 ligand (PD-L1) inhibitors have shown activity in variety of cancers, to this point there is minimal evidence of activity in mCRPC. This is a report of avelumab, anti-PDL1 in mCRPC patients (pts). Methods: This is an expansion cohort of the first in human, phase I trial (JAVELIN Solid Tumor; EMR100070-001) that evaluated 10 mg/kg of avelumab in pts with mCRPC who had progressive disease (PD) on previous treatment. Pts who had PD on an androgen receptor antagonist (ARA) could enroll on trial and continue their ARA. Avelumab was administered as a 1-hour intravenous infusion every 2 weeks (w) with restaging scans every 6 w. Prostate cancer working group 2 criteria were used to determine PD. Results: 18 patients were enrolled on this cohort; the median age of pts was 67 years. Median on study PSA was 11ng/mL. 11 pts had Gleason score (GS) ≥ 8 and 7 had GS of 7. 3 pts had previous chemotherapy with docetaxel, 8 pts received previous vaccine treatment including 4 pts with sipuleucel-T and 4 pts with Prostvac. Overall avelumab treatment appears safe and tolerable. 15 pts experienced grade ≤ 2 treatment related adverse events (TRAEs), fatigue being the most common one. 4 pts developed treatment related hypothyroidism, 3 with grade 2 and 1 with grade 1. In addition, 2 pts had grade 3 asymptomatic TRAEs (amylase & lipase elevations). 7 pts had stable disease (SD) > 24 w post treatment, 6 pts had PD after first restaging scans at 6 w which was reconfirmed in 2nd restaging scan at 12 w. PSA doubling time (PSADT) prior to avelumab was compared with PSADT after 3 months (m) of treatment. Among 17 pts with available data, 3 pts had a prolonged PSADT which was defined at 3 m (twice as high as on-study PSADT), 7 pts had stable PSADT and 7 had decreased PSADT. 5 of 18 pts enrolled while on enzalutamide with a rising PSA. Among these pts 1 had prolonged PSADT, 2 had a stable PSADT and 2 with decreased PSADT after 3 m of follow up. 3 of 5 pts had SD > 24 m, 1 had SD for 13 w and 1 had PD at first restaging scans. Conclusions: These data provide safety data of avelumab on a population of pts with mCRPC. Immune analysis is under way to determine correlation with immune responses in the pts on this trial that had prolonged SD. Clinical trial information: NCT01772004.
A phase II trial of abiraterone acetate (AA) without prednisone in castration resistant prostate cancer (CRPC).
Authors: McKay Rana R. , Werner Lillian , Jones Alexandra , Choudhury Atish Dipankar , Pomerantz Mark , Sweeney Christopher , Bubley Glenn J. , Slovin Susan F. , Morris Michael J. , Kantoff Philip W. , Taplin Mary-Ellen
Published: September 2018

5040

Background: AA blocks CYP17 and suppresses adrenal androgens and glucocorticoids. Given the risk of mineralocorticoid excess (ME), AA is administered with corticosteroids. In this phase II multicenter, single-arm study, we assess the safety of AA without steroids in CRPC. The primary objective is to determine the proportion of men requiring prednisone to manage ME. Methods: Eligible patients had CRPC with controlled blood pressure (BP) ( < 140/90 on ≤3 agents) and a normal or ≥3.5 mmol/L potassium. Patients initially received AA (1000 mg daily) alone. Patients who developed a BP ≥ 140/90 were treated with anti-hypertensives (HTN) and/or a mineralocorticoid antagonist (MA) prior to steroids. Hypokalemia was treated with supplementation or a MA. Patients with persistent or severe ME were initiated on prednisone (5 mg twice daily). To assess response to steroids, prednisone was added to AA at PSA progression. Therapy was continued until radiographic progression, toxicity, or withdrawal. Results: 60 patients were enrolled of whom 51 (83%) had metastases 16 (27%) received prior chemotherapy, 6 (10%) enzalutamide, and 4 (7%) ketoconazole. Grade (G) 3-4 adverse events (AEs) of interest included HTN (G3 n = 8, 13%; G4 n = 1, 2%), hypokalemia (G3 n = 4, 7%; G4 n = 0), fatigue (G3 n = 1, 2%; G4 n = 0). There was no G ≥3 edema. 9 patients (15%) initiated prednisone for toxicity: HTN (n = 3, 5%), hypokalemia (n = 4, 7%), fatigue (n = 2, 3%). Baseline PSA was 15.4 ng/mL. Time to nadir PSA was 2.5 months (IQR 1.4, 6.3) and median nadir PSA was 2.1 ng/mL. 67% of patients (n = 40) experienced a ≥50% PSA decline and 35% (n = 21) experienced a ≥90% decline. 19 patients (32%) initiated prednisone for PSA progression. Median time to prednisone initiation in patients with PSA progression was 6.1 months (IQR 4.9, 11.7); 5 patients (8.3%) had a PSA decline and 1 achieved a ≥50% decline. Levels of corticosteroids will be reported. Conclusions: In CRPC, AA without steroids is feasible, however clinically significant AEs, particularly HTN, can occur in a minority of patients. HTN and hypokalemia can be treated with anti-HTN agents or potassium without steroids in the majority. Use of AA without prednisone needs to be balanced with the potential risk of toxicity. Clinical trial information: NCT02025010.
Targeted sequencing in a phase III trial of luminal breast cancer: Identification of novel targets.
Authors: Bartlett John , Kalatskaya Irina , Yousif Fouad , Bayani Jane , Trinh Quang M , Heisler Lawrence , Timms Lee , Lee Shawna , Buchner Nicholas , Milacic Marija , Rothfels Karen , Crozier Cheryl , Drake Camilla , Hasenburg Annette , Kieback Dirk G , Rea Daniel , McPherson John , Boutros Paul Christopher , Stein Lincoln D
Published: September 2018

505

Background: The International Cancer Genome Consortium and The Cancer Genome Atlas have had a global transformative impact on our understanding of cancer. These programs have mapped the genomic landscape of common and rare tumors setting the scene for a comprehensive change in the approach to cancer diagnosis and treatment. However, the task remains incomplete until these mutational events are linked to clinical outcomes in the context of current therapeutic intervention to drive future stratified medicine approaches. Methods: We performed targeted sequencing in patients from the Tamoxifen Exemestane Adjuvant Multicentre trial. DNA was extracted and a 101 gene panel analysed using a novel mutation calling pipeline. Both a priori and machine learning analyses were performed using distant recurrence free survival as the primary endpoint. Results: In 1,491 successfully analyzed samples 1,070 (71.76%) samples exhibited at least one single nucleotide mutation (range 0-94, 1.828+/-0.133, mean+/-s.e.). 98/101 genes were mutated in at least one patient. Only variants in PIK3CA, TP53, MLL3, CDH1 were detected in 5% or more of samples. Twenty genes were associated with increased risk of recurrence in multivariate analyses corrected for clinic-pathological variables, 50% of these genes were involved in transcriptional regulation or RNA/protein processing. In a multivariate analysis, two combined signalling modules were independently prognostic for residual risk following hormone therapy (HRvalidation 3.10 95%CI 1.78-5.40 and HRvalidation 2.70 95%CI 1.57-4.64). Conclusions: We successfully performed a signalling pathway-based targeted sequencing analysis within predefined signalling modules. In supervised and unsupervised analyses we identified multiple signalling cassettes linked to poor outcome in patients with ER+ve breast cancers treated with modern endocrine therapy in the context of a phase III clinical trial. These results identify novel candidates as targets to treat endocrine refractory breast cancers.
The plasma lipidome in castration-resistant prostate cancer.
Authors: Horvath Lisa , Lin Hui-Ming , Mahon Kate Lynette , Weir Jacquelyn , Mundra Piyushkumar , Spielman Calan , Briscoe Karen P. , Gurney Howard , Mallesara Girish , Marx Gavin M. , Stockler Martin R. , Parton Robert , Hoy Andrew , Daly Roger J. , Meikle Peter
Published: September 2018

5055

Background: Biomarker studies of metastatic castration-resistant prostate cancer (CRPC) have mainly focused on changes in the cancer, however, the host environment and its interactions with cancer is increasingly important, especially given the increasing association of PC outcomes and obesity. We sought associations between the plasma lipidome and clinical outcome in CRPC. Methods: Plasma samples were obtained from a Phase 1 discovery cohort of 96 CRPC patients before and after the first cycle of docetaxel chemotherapy. Lipidomic profiling of the plasma samples was performed by liquid chromatography and electrospray ionisation-tandem mass spectrometry. Results were subsequently assessed in a Phase 2 validation cohort of 63 CRPC patients. Results: Lipidomic profiling detected 323 lipid species in plasma samples from the Phase 1 cohort. Patients could be classified into two subgroups with significant survival differences according to their baseline lipidomic profiles (median overall survival 13.7 vs 21.7 months; HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The baseline levels of 46 lipids were individually prognostic (p < 0.01) and predominantly sphingolipids. A prognostic three-lipid signature was derived (ceramide (d18:1/24:1), sphingomyelin (d18:2/16:0), phosphatidylcholine (16:0/16:0)) (11.7 versus 21.7 months, p = 0.00001; HR 2.94, 95% CI 1.80-4.81, p = 0.00002). The signature was associated with shorter overall survival in the Phase 2 cohort (HR 4.78, 95% CI 2.06-11.1, p = 0.0003), and was an independent prognostic factor when modeled with clinicopathological factors and metabolic characteristics (BMI, cholesterol and triacylglycerol). The AUC of ROC analysis of 12 month survival for a clinicopathological model (AUC 0.70, 95% CI 0.54-0.87, p = 0.03) was enhanced by the addition of the 3-lipid signature (AUC 0.73, 95% CI 0.57-0.89, p = 0.01). Conclusions: Our study is the first to comprehensively profile the plasma lipidome of men with CRPC using cutting-edge lipidomic profiling technology, to identify a plasma lipid signature that can reproducibly predict outcome in CRPC and can improve on clinicopathological models. Therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.
Association of androgen receptor (AR) status in plasma DNA with outcome on enzalutamide (enza) or abiraterone (abi) for castration resistant prostate cancer (CRPC).
Authors: Conteduca Vincenza , Wetterskog Daniel , Sharabiani Mansour Taghavi Azar , Jayaram Anuradha , Salvi Samanta , Romanel Alessandro , Lolli Cristian , Casadio Valentina , Gurioli Giorgia , Amadori Dino , Gasi Tandefelt Delila , Wingate Anna , Dearnaley David P. , Demichelis Francesca , De Giorgi Ugo , González-Billalabeitia Enrique , Attard Gerhardt
Published: September 2018

5060

Background: There is an urgent need to identify biomarkers to guide personalized therapy in CRPC. We aimed to clinically qualify the association of AR status in plasma DNA with worse outcome in pre- and post-docetaxel (doc) CRPC. Methods: We used droplet digital (dd)PCR to assess AR copy number (CN) and mutations (mut) (2105T > A (p.L702H) and 2632A > G (p.T878A) status in plasma DNA from 171 patients (pts) treated with abi/enza in biomarker protocols at 2 institutions. The aim to evaluate plasma AR was defined after sample collection but prior to analysis. Results: We first optimised multiplex ddPCR to accurately define AR status and identified an AR CN cutpoint = 2.01 as having the greatest likelihood to split pts into 2 prognostic groups. We confirmed a strong agreement between ddPCR and NGS for quantitating AR CN and mut allelic frequency (Bland-Altman test: mean difference -0.02 95%CI -2.45 to 2.41; mean difference -0.01 95%CI -0.015 to 0.016 respectively). AR CN gain was observed in 10 (14%) pre- and 33 (34%) postdoc pts and associated with a worse OS (HR 3.98 95%CI 1.74-9.10 p < 0.001; HR 3.81 95%CI 2.28-6.37 p < 0.001 respectively), PFS (HR 2.18 95%CI 1.08-4.39 p = 0.03; HR 1.95 95%CI 1.23-3.11 p = 0.01 respectively) and PSA decline ≥50% (OR 4.7 95%CI 1.17-19.17 p = 0.035; OR 5.0 95%CI 1.70-14.91 p = 0.003 respectively). AR mut were observed in 8 (11%) postdoc but no pre-doc abi-treated pts and also associated with worse OS (HR 3.26 95%CI 1.47-not reached p = 0.004). There was no interaction between AR and doc status (p = 0.83 for OS, p = 0.99 for PFS). Multivariate analysis, adjusting for AR CN and mut, previous doc, double stranded DNA concentration, LDH, confirmed AR status was independently associated with OS (HR 3.77 95%CI 2.42-5.88 p < 0.001 and HR 2.76 95%CI 1.26-6.07 p = 0.011 for AR CN and mut respectively) and PFS (HR 1.96 95% CI 1.32-2.93 p = 0.001). Conclusions: Plasma AR status assessment using multiplex ddPCR identifies CRPC with worse outcome to enza/abi in pre/postdoc CRPC. Additional clinical qualification is available from the PREMIERE study (Grande et al;ASCO2017;Abstract#). Prospective evaluation of treatment decisions based on plasma AR is now required.
A secondary analysis of PSA response in NRG Oncology/RTOG 9902: A phase III trial of adjuvant chemotherapy with androgen suppression and radiation for high-risk prostate cancer (CaP).
Authors: Mihalcik Stephen Andrew , Regan Meredith M. , Rosenthal Seth A. , Bubley Glenn J. , Pienta Kenneth J. , Gomella Leonard G. , Grignon David A. , Hartford Alan C , Morginstin Mark S. , Michalski Jeff M. , Rajan Raghu , McDonald Andrew Michael , Dominello Michael M. , Atkins James Norman , Jones Christopher U , Moughan Jennifer , Sandler Howard M. , Kaplan Irving D.
Published: September 2018

5078

Background: RTOG 9902 was a randomized controlled trial of the addition of adjuvant chemotherapy (CT; paclitaxel, oral etoposide, and estramustine x4 cycles) to 24 mo of androgen suppression (AS) and radiation (RT) for patients (pts) with high-risk CaP., beginning with an initial 4 mo of AS; RT began after 2 mo. 9902 accrued 397 pts and closed early due to excess toxicity. At a median follow-up of 9.2 years, there was no benefit to CT, but it is hypothesized that a subset analysis by post-RT PSA identifies pts that benefit from treatment intensification with CT. Methods: Post-RT PSA status was dichotomized at > 0.2 ng/mL within 1 mo of RT. Landmark analysis redefined starting times for disease-free survival (DFS), time to distant metastasis (TDM) and overall survival (OS) at 16 weeks post-RT (36 weeks post-randomization) when CT was planned to complete. Pts were excluded if they did not get RT or assigned CT, or experienced DFS events/lost to follow-up < 36 wks post-randomization. Hazard ratios (HR), 95% confidence intervals (CI), and PSA-by-treatment interaction were estimated by Cox or competing-risks regression. Results: 333 pts were analyzed: 190 without and 143 with CT. 37% of pts had a post-RT PSA ≤0.2, 34% > 0.2, and 29% no recorded PSA in the defined interval. CT was associated with improved DFS for pts with PSA > 0.2 (HR 0.59, 0.38-0.91), but not for those with PSA ≤0.2 (HR 0.94, 0.60-1.46; interaction p = 0.13). This association, for those with PSA > 0.2, persisted in those pts who received the full course of CT and trended in the same direction for pts receiving 1-3 cycles. CT was associated with a trend toward improved TDM in the PSA > 0.2 group (HR 0.56, 0.23-1.35) and not in the PSA≤0.2 group (HR 1.31, 0.36-4.70), based on 32 pts with metastases. OS did not show the same pattern (PSA > 0.2: HR 0.98, 0.55-1.77; PSA≤0.2: HR 0.57, 0.29-1.13). Conclusions: This analysis suggests that men with high-risk CaP and suboptimal response to AS+RT, as identified by post-RT PSA > 0.2, may benefit from adjuvant CT. Prospective trials using contemporary CT (e.g. docetaxel) will help optimize treatment for these men. NRG-GU002, recently activated, is addressing this issue.
SWOG S0221 updated: Randomized comparison of chemotherapy schedules in breast cancer adjuvant therapy.
Authors: Budd G. Thomas , Barlow William E. , Moore Halle C. F. , Hobday Timothy J. , Stewart James A. , Isaacs Claudine , Salim Muhammad , Cho Jonathan K. , Rinn Kristine , Albain Kathy S. , Chew Helen K. , Burton Gary Von , Moore Timothy David , Srkalovic Gordan , McGregor Bradley Alexander , Flaherty Lawrence E. , Livingston Robert B. , Lew Danika L , Gralow Julie , Hortobagyi Gabriel N.
Published: September 2018

521

Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P<0.001) than the HER2-positive or ER/PR+/HER2- subsets, with 5 year DFS of 75% vs 83% and 84%, respectively. While we previously found in the triple negative subset that the arm using q 2 weeks for both AC and paclitaxel was marginally superior, the differences among the arms are no longer significant for DFS (p=0.12) or OS (p=0.11). Among the 578 pts assigned ACx4 and randomized to Pw v P2 there were no overall differences in DFS (p=0.70) or OS (p=0.63) after 4.4 years median follow-up. Conclusions: There were no significant differences in DFS or OS between any of the schedules with extended follow-up in the original cohort and no difference in outcome by paclitaxel schedule for the 578 additional patients in the revised protocol. Either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564.