bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I clinical trials as a therapeutic option for patients with metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W , Alhalabi Omar , Meric-Bernstam Funda , Naing Aung , Jonasch Eric , Msaouel Pavlos , Piha-Paul Sarina Anne , Hong David S. , Pant Shubham , Yap Timothy A , Campbell Erick , Le Hung , Tannir Nizar M. , Roszik Jason , Subbiah Vivek 
Published: May 2020

5073 Background: Immune checkpoint inhibitors, multi-kinase VEGF agents, and mTOR inhibitors are approved for mRCC. Due to the overlapping mechanisms of action of the twelve approved therapies for mRCC, select patients are referred for phase I clinical trials after progression on multiple lines of treatment. We sought to evaluate the efficacy of phase I trials in patients with mRCC. Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center. Baseline clinical characteristics and outcomes data were retrospectively collected. The historical control was a study of 1112 patients with mRCC who received third-line treatment in the IMDC database (PMID: 27318422). Time to event endpoints were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Between 2014 and 2019, there were 106 cases where 82 patients with mRCC were enrolled in a phase I clinical trials (40 unique trials). 30% (32/108) of the cases were in patients with non-clear cell RCC (nccRCC), and the most prevalent nccRCC histologies were papillary (n = 7) and renal medullary carcinoma (n = 7). The median number of prior systemic therapies was 2 (range 0-9). Across the entire cohort, median PFS was 5.9 months (m), median OS was 31.2 m, and the ORR was 23% (Table). In patients who received at least two prior lines of therapy (n = 70), the median PFS was 4.8 m and median OS was 24.9 m. In patients with metastatic nccRCC, median OS, PFS, and ORR were numerically lower, but statistically did not contradict the supposition that these outcomes did not differ from ccRCC (Table). Conclusions: In the largest pooled phase I clinical trial experience for patients with mRCC, phase I trials may have therapeutic value when compared to historical controls, where median PFS was 3.9 m, median OS was 12.4 m, and ORR was 10.5%. Patients with all histologies of mRCC may derive clinical benefit from phase I clinical trials, yet patients with ccRCC had numerically better outcomes. Patients with mRCC should be considered for phase I clinical trials. [Table: see text]
Immune infiltration and angiogenesis as markers of outcome in the post-nephrectomy setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).
Authors: Hakimi A. Ari , Voss Martin H , Kuo Fengshen , Silagy Andrew W. , Marker Mahtab , Reising Albert , Millholland John , Chan Timothy An-thy , Russo Paul , Motzer Robert J. 
Published: May 2020

5082 Background: Defined stromal and immune features of the tumor microenvironment (TME) have proven relevant for outcomes with systemic therapy in advanced clear cell renal cell carcinoma (ccRCC). We hypothesized that these may matter beyond therapeutic applications and could be relevant much earlier in the disease course. We sought to study the TME in high risk ccRCC patients undergoing definitive surgery. Methods: Clinical, pathologic, immunohistochemical, and whole-genome microarray data were acquired on 236 out of 769 patients in the Placebo arm of PROTECT trial (NCT01235962 - pazopanib vs placebo). Transcriptomic scores assessing angiogenesis and myeloid infiltration with individual annotations above/below median were used to categorize patients into four groups (angiogenesis high vs. low; myeloid high vs. low). We tested categorical association with disease free (DFS) and overall survival (OS) using logrank testing and assessed interdependence with relevant clinicopathologic variables, including the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Tumors from236 patients were available for analysis. Overall, 37% developed metastatic recurrence and 81% were alive at last follow up. On univariate analysis increasing tumor stage, higher UISS score, and angiogenesis/myeloid subgroups (high – H and low – L) were associated with worse DFS and OS (all p values <0.05). On multivariate analysis TME subgroups remained significant for worse DFS and OS (Table). Conclusions: Microenvironmental subgroups stratified into angiogenic and myeloid expression profiles carry independent prognostic significance and should be further explored to guide future biomarker-directed adjuvant trials. Clinical trial information: NCT01235962 . [Table: see text]
Breast cancer index (BCI) predicts benefit of two-and-a-half versus five years of extended endocrine therapy in HR+ breast cancer patients treated in the ideal trial.
Authors: Liefers Gerrit-Jan , Noordhoek Iris , Treuner Kai , Putter Hein , Zhang Yi , Meershoek – Klein Kranenbarg Elma , Wong Jenna , Van De Velde Cornelis J. H. , Schnabel Catherine A. 
Published: May 2020

512 Background: For postmenopausal women with hormone receptor positive (HR+) breast cancer, the optimal duration of extended endocrine therapy (EET), after completing 5 years of initial aromatase inhibitor (AI)–based adjuvant therapy, remains unclear. BCI [HOXB13/IL17BR (H/I)] is a gene expression-based biomarker that has been demonstrated to predict EET benefit in the MA.17 and Trans-aTTom studies in patients treated with adjuvant tamoxifen. The current study examined the ability of BCI (H/I) to predict endocrine benefit from 2.5 vs. 5 years of extended letrozole in the IDEAL trial. Methods: All patients with available tumor specimens were eligible for this blinded prospective-retrospective study. The primary endpoint was Recurrence-Free Interval (RFI). Median follow-up was 9.1 years from randomization. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the differential benefit of EET with statistical significance of the interaction between BCI (H/I) and treatment assessed by likelihood ratio test. Results: 908 HR+ patients (73% pN+, median 59y, 45% pT1, 48% pT2, disease free at 2.5 years) were included, with 88% and 68% receiving prior treatment with an AI or chemotherapy, respectively. BCI by H/I status (High vs. Low) was significantly predictive of response from extended letrozole in the overall (N = 908) and pN+ (N = 664) cohorts. Notably, BCI (H/I) predicted EET benefit in patients that received any primary adjuvant therapy with an AI (N = 794). Treatment to biomarker interaction was significant in the overall (p = 0.045), pN+ (p = 0.029) and any prior AI (p = 0.025) cohorts, adjusted for age, pT stage, grade, nodal status, prior endocrine therapy and prior chemotherapy. Conclusions: Novel findings from this study demonstrate that BCI predicts endocrine benefit from extended letrozole in postmenopausal patients treated with primary adjuvant AI. These results support the growing body of evidence that BCI by H/I status predicts preferential endocrine response in distinct subgroups of patients, and further support its role as an important genomic tool to inform the risk-benefit regarding duration of extended endocrine therapy. Clinical trial information: NTR3077, BOOG 2006-05, Eudra-CT 2006-003958-16 . [Table: see text]
Validation of MAF biomarker for response prediction to adjuvant bisphosphonates in 2 clinical trials: AZURE and NSABP-B34.
Authors: Paterson Alexander H. G. , Anderson Stewart J. , Gomis Roger , Jean-Mairet@inbiomotion.com Joel , Tercero Juan-Carlos , Lucas Peter , Mamounas Eleftherios P. 
Published: May 2020

513 Background: An Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis indicates that adjuvant bisphosphonates increase time to bone recurrence and survival in postmenopausal breast cancer patients, but results of individual trials have been inconclusive. Retrospective analyses of AZURE, a trial of adjuvant zoledronic acid, showed MAF (a transcription factor of the AP-1 family) amplification status predicted bisphosphonate benefit independently of menopause for invasive disease-free survival (IDFS) and overall survival (OS). Validation of MAF amplification status as a potential companion diagnostic for adjuvant bisphosphonates was confirmed using NSABP-B34 specimens. Methods: The randomized, placebo-controlled NSABP B-34 study of women with stage 1-3 breast cancer were assigned to adjuvant systemic therapy plus oral clodronate 1600 mg daily or placebo for 3 years. The primary endpoint was disease-free survival (DFS) with overall survival (OS) as a secondary outcome. MAF amplification was assessed by fluorescence in-situ hybridization on anonymized sections of breast tumor tissue in all patients with tumor samples and performed in a laboratory blind to treatment assignment. Protocol and analysis plans were pre-specified. Disease outcomes were analysed using intention to treat principles. Results: 2496 B-34 patients contributed tumor samples (from 2001-2004), of whom 1883 (75%) were evaluable (947 placebo and 936 clodronate). 1515 (80%) tumors were MAF negative (766 placebo and 749 clodronate) and 368 were MAF positive. At median follow-up of 108 months, MAF was prognostic for DFS, OS and bone-metastasis-free survival in the control group (MAF-positive vs MAF-negative: HRDFS=1·39, 95%CI 1·01-1·92; p=0.045; HROS=1·59, 95%CI 1·08-2·33; p=0.018; HRBM=2·03, 95%CI 1·13-3·68; p=0.016). In patients with MAF-negative tumors, clodronate gave higher DFS and OS than controls at 60 months (HRDFS=0·70, 95%CI 0·51-0·94; p=0.020 and HROS=0·59, 95%CI 0·37-0·93; p=0.024), the latter maintained through follow-up (HROS=0·74, 95%CI 0·54-1.00; p=0.047), but not in patients with MAF-positive tumors - consistent with previous AZURE results. Conclusions: MAF benefit prediction from adjuvant bisphosphonates was confirmed using specimens from 2 randomized clinical trials (AZURE and NSABP-B-34) conducted and analyzed in similar manner using the same validated tests and clinical endpoints. These results are evidence towards introducing MAF testing into clinical practice.
Comprehensive profiling of androgen receptor-positive (AR+) triple-negative breast cancer (TNBC) patients (pts) treated with standard neoadjuvant therapy (NAT) +/- enzalutamide.
Authors: Lim Bora , Seth Sahil , Huo Lei , Layman Rachel M. , Valero Vicente , Thompson Alastair Mark , White Jason B , Litton Jennifer Keating , Damodaran Senthil , Candelaria Rosalind P , Arun Banu , Rauch Gaiane M , Murthy Rashmi Krishna , Ding Qingqing , Symmans William Fraser , Zhao Li , Zhang Jianjun , Tripathy Debu , Moulder Stacy L. , Ueno Naoto T. 
Published: May 2020

517 Background: The luminal androgen receptor (LAR) subtype of TNBC has a low pathologic complete response (pCR) rate after NAT. We determined the pCR rate of the enzalutamide and paclitaxel (ZT) regimen for pts with anthracycline-insensitive AR+ TNBC (NCT02689427), and related biomarkers. Methods: ARTEMIS (NCT02276443) is a non-randomized trial to determine if NAT can be used to personalized therapy. Pts received 4 cycles of doxorubicin-based NAT (AC). Pts with insensitive disease by imaging were offered clinical trials as the second phase of NAT based upon molecular profiling of pre-treatment biopsies. Immunohistochemistry (IHC) of AR+≥10% was the threshold for selecting ZT (enzalutamide 160 or 120 mg PO qD + paclitaxel 80 mg/m2 qW for 12 cycles). pCR was determined by surgery after NAT. Trial had two-stage Phase II design, and we report the completed first stage. We evaluated the concordance between Vanderbilt LAR subtype by molecular profiling (microarray and RNAseq) and IHC %AR+ cells. Frequency of PI3K pathway alterations within the LAR subtype was assessed. Results: 267 pts had tumors profiled by IHC, 220 by microarray, 187 by RNAseq and 197 by whole exome sequencing. 96 pts had post-AC RNAseq. LAR scores from both RNAseq and microarray profiling (n = 139) were highly concordant (R = 0.89, P < 0.001) and identified ~10% of TNBCs tested as LAR. The %AR+ cells from IHC correlated with LAR subtype scores according to RNAseq (R = 0.6, P < 0.001), with a cut-point of ≥30% AR+ having the best concordance with LAR subtype. Unlike other subtypes, by serial profiling, LAR TNBCs did not change subtype signatures after exposure to AC. LAR TNBCs had low rates of pCR (23%) and high rates of PI3K pathway activating aberrations (85%); however PI3K aberrations did not correlate with pCR. Seventeen patients with AC-insensitive TNBC received ZT. Five of 15 patients (33.3%) had responses (pCR or RCB-I). Toxicities are Grade (Gr) 4 syncope (n = 1), Gr3 abnormal liver function (n = 2), Gr3 neutropenia (n = 4). IHC & LAR subtype scores did not statistically associate with response to ZT (P = 0.8, P = 0.9). However, all responders to ZT had an upregulated androgen response pathway (ssGSEA Z > 1) as measured by transcriptomic analysis in pre-treatment biopsies analysis (P = 0.05, ppv = 0.56, npv = 1). Conclusions: The LAR TNBC subtype has a low pCR rate to NAT. Among pts with AC-insensitive TNBC, baseline upregulated androgen response pathway and LAR subtype may benefit from the ZT regimen, potentially by PI3K targeting. Clinical trial information: NCT02689427 .
Dementia risk among post-menopausal women treated with endocrine therapy for early-stage breast cancer in Ontario, Canada.
Authors: Blanchette Phillip S. , Lam Melody , Le Britney , Richard Lucie , Shariff Salimah , Pritchard Kathleen I. , Raphael Jacques , Vandenberg Theodore A. , Fernandes Ricardo , Desautels Danielle , Chan Kelvin K. , Earle Craig 
Published: May 2020

521 Background: The association between anti-estrogen therapy and risk of dementia remains controversial. We performed a population-based real-world study investigating the association between endocrine therapy use and dementia. Methods: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005-2012. Patients were classified by use of either an aromatase inhibitor or tamoxifen and followed to measure an unadjusted cumulative incidence of developing dementia. A multivariable analysis adjusting for age, income quintile, medical comorbidities, and duration of endocrine therapy was completed using a Cox-proportional hazards model. Results: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor and 27% with tamoxifen. The median age was 73 years (IQR 69-78), 64% of patients were treated with lumpectomy, and 19% received adjuvant chemotherapy. The unadjusted event rate for developing dementia was Hazard Ratio (HR)= 0.70 (95% confidence interval (CI)=0.63-0.78, p-value<0.0001) among patients receiving an aromatase inhibitor versus tamoxifen and the 5-year dementia incidence rate was 7.4% versus 9.2% respectively. Our multivariable analysis showed a significant decrease in the rate of dementia in patients treated with an aromatase inhibitor compared to tamoxifen (HR=0.88, 95% CI 0.78-0.98, p-value=0.02) with a median of 5.9 years of follow-up. Factors associated with the development of dementia included older age, previous history of ischemic heart disease, diabetes, hypertension and stroke. Duration of endocrine therapy and previous use of adjuvant chemotherapy were not associated with dementia in our study. Conclusions: This investigation indicates that use of aromatase inhibitors compared to tamoxifen is associated with a lower risk of developing dementia among post-menopausal breast cancer patients. Further prospective studies investigating the neurocognitive effects of endocrine therapy are warranted.
Tumor-infiltrating lymphocytes in ipsilateral breast tumor recurrences predict prognosis.
Authors: Stenmark Tullberg Axel , Nimeus-Malmström Emma , Killander Fredrika , Sjöström Martin , Puttonen Henri A.J. , Feng Felix Y , Kovacs Aniko , Lundstedt Dan , Holmberg Erik , Karlsson Per 
Published: May 2020

546 Background: The antitumoral immune response is dynamic and changes with tumor progression. Previous studies show that immunohistochemical (IHC) assessment of TILs in local recurrences can predict prognosis. It is not clear how adjuvant radiotherapy (RT) can alter the local immune response or if gene expression analyses of TILs in recurrences can provide prognostic information. Methods: Matched biopsies from primary tumors and ipsilateral breast tumor recurrences (IBTRs) from the randomized SweBCG91RT trial were assessed for TILs. Analyses were performed using gene expression (86 matched pairs) and IHC assessment (126 matched pairs). Results: The median time to IBTR was 8.0 years among irradiated patients and 3.6 years among unirradiated patients. In the gene expression analyses, higher absolute values of CD8+ T cells, CD4+ effector memory and CD8+ effector memory T cells in the recurrence could significantly predict a decreased risk of subsequent distant metastasis. In addition, a net increase of these cells in the IBTR compared to the primary tumor was associated with a significantly lower risk of metastasis. TILs did not change significantly between the matched tumors for the whole group or among irradiated patients versus unirradiated patients in the gene expression or IHC analyses. Surprisingly, the group with unchanged TILs levels as measured by IHC had the lowest risk of metastasis while an increase or a decrease in TILs was significantly associated with an increased risk. Conclusions: Cytotoxic and memory T cells in the recurrence protect against subsequent distant metastasis although IHC measurement of TILs could not confirm these results. No significant differences in TILs infiltration between irradiated versus unirradiated patients could be determined in the recurrences. Further analyses including changes of subtypes between the primary tumor and the recurrence will be presented.
TheraP: A randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: Initial results (ANZUP protocol 1603).
Authors: Hofman Michael S , Emmett Louise , Sandhu Shahneen Kaur , Iravani Amir , Joshua Anthony M. , Goh Jeffrey C. , Pattison David A. , Tan Thean Hsiang , Kirkwood Ian D. , Ng Siobhan , Francis Roslyn J. , Gedye Craig , Rutherford Natalie K. , Zhang Alison Yan , McJannett Margaret Mary , Stockler Martin R. , Violet John A. , Williams Scott , Martin Andrew James , Davis Ian D. 
Published: May 2020

5500 Background: LuPSMA is a radiolabeled small molecule that delivers therapeutic β-radiation to PSMA-expressing tumors. Encouraging efficacy and safety has been shown in non-randomized studies of mCRPC. TheraP is a randomized phase II trial comparing LuPSMA vs cabazitaxel in men with mCRPC progressing after docetaxel. Methods: Men with mCRPC, and imaging with 68Ga-PSMA-11 and 18F-FDG PET/CT that confirmed high PSMA-expression and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8GBq q6weeks up to 6 cycles) vs cabazitaxel (20mg/m2 q3weeks up to 10 cycles); stratified by disease burden (>20 vs ≤20 sites), prior novel antiandrogens (NAA; abiraterone or enzalutamide), and study site. The primary endpoint was PSA response rate (PSA50-RR) defined by ≥50% reduction. Secondary efficacy endpoints included PSA-progression-free survival (PSA-PFS) and overall survival (OS). Data cut-off was 31DEC19 at this first pre-specified analysis. Results: 200 (median age 72 y, prior NAA 91%, >20 lesions 78%) of 291 PET screened men were randomised to LuPSMA (N=99) or cabazitaxel (N=101). 17 patients withdrew or died before receiving study treatment (1 LuPSMA vs 16 cabazitaxel). The PSA50-RR was higher in those assigned LuPSMA than cabazitaxel (65/99 [66%; 95%CI 56-75] vs 37/101 [37%; 95%CI 27-46]; P<0.001). At a median follow-up of 11.3 months, LuPSMA significantly improved PSA-PFS (HR 0.63, 95%CI 0.45-0.88, P=0.007; 143 events with next pre-specified analysis planned after 170 events). Efficacy results were similar when analyses were restricted to per-protocol treated men. OS data remains immature (57 deaths). Grade III-IV adverse events (AEs) occurred in 31/98 (32%) LuPSMA-treated men vs 42/85 (49%) in cabazitaxel-treated men. Discontinuations for toxicity occurred in 1/98 (1%) LuPSMA vs 3/85 (4%) cabazitaxel-treated. There were no treatment-related deaths. Conclusions: In men with docetaxel-treated mCRPC, LuPSMA was more active (PSA50-RR) than cabazitaxel with relatively fewer G3-4 AEs and PSA-PFS favoring LuPSMA. Clinical trial information: NCT03392428 .
Accuracy of 68Ga-PSMA-11 for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic lymph node dissection: A multicenter prospective phase III imaging study.
Authors: Hope Thomas A , Armstrong Wesley R , Murthy Vishnu , Lawhn Heath Courtney , Behr Spencer , Barbato Francesco , Ceci Francesco , Farolfi Andrea , Schwarzenboeck Sarah , Unterrainer Marcus , Zacho Helle , Cooperberg Matthew R. , Nguyen Hao Gia , Carroll Peter , Reiter Robert Evan , Holden Stuart , Fendler Wolfgang Peter , Eiber Matthias , Czernin Johannes , Calais Jeremie 
Published: May 2020

5502 Background: To determine the accuracy of 68Ga-PSMA-11 PET for the detection of pelvic nodal metastases (N1) compared to histopathology at time of radical prostatectomy (RP). Methods: This is a prospective multicenter single-arm open-label phase 3 imaging trial. Patients with intermediate to high risk prostate cancer (PCa) considered for RP with lymph node dissection (PLND) were enrolled at the University of California, Los Angeles (UCLA) and at the San Francisco (UCSF) (NCT03368547, NCT02611882, NCT02919111), and underwent one 68Ga-PSMA-11 PET. The primary endpoint was the sensitivity (Se) and specificity (Sp) of 68Ga-PSMA-11 PET for the N1 detection compared to PLND histopathology (reference-standard) on a per patient basis using nodal region-based correlation. Each scan was read by three blinded independent central readers (BICR). Consensus was based on majority rule. Results: From December 2015 to August 2019, 633 patients underwent one 68Ga-PSMA-11 PET for primary staging, and 277/633 (44%) subsequently underwent RP and PLND. The median initial PSA was 11.1 [0.04-147]. 75/277 patients (27%) had N1 disease per histopathology. Using a regional based analysis, Se, Sp, positive predictive value (PPV) and negative predictive value (NPV) for N1 detection was 0.40 [0.34, 0.46], 0.95 [0.92, 0.97], 0.75 [0.70, 0.80], 0.81 [0.76, 0.85], respectively. Se was higher for patients with higher PSA: 0.29 [0.24, 0.35] for PSA < 11 ng/ml versus 0.48 [0.42, 0.54] for PSA > 11. Se was higher when the nodes were larger: 0.30 [0.25, 0.36] for nodes < 10 mm versus 0.68 [0.63, 0.74] for nodes > 10. The average node size in true positive patients was 10 mm versus 4 mm in false negative patients. Conclusions: In intermediate to high risk PCa patients who underwent RP and PLND, 68Ga-PSMA-11 PET detected pelvic nodal metastases with a sensitivity of 0.40 and a specificity of 0.95. Higher PSAs and larger node size correlated with increased sensitivity. Clinical trial information: NCT03368547, NCT02611882, NCT02919111 .