bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a genomic-clinical classifier for predicting progression after radical cystectomy in patients with muscle invasive bladder cancer.
Authors: Mitra Anirban Pradip , Erho Nicholas , Lam Lucia L.C. , Vergara Ismael A. , Sierocinski Thomas , Zimmermann Benedikt , Haddad Zaid , Ghadessi Mercedeh , Crisan Anamaria , Triche Timothy J. , Daneshmand Siamak , Buerki Christine , Davicioni Elai , Black Peter C.
Published: March 2020

4542

Background: The mainstay of muscle-invasive bladder cancer treatment is surgical resection with/without multi-agent chemotherapy. Management decisions are based on a small number of clinical and pathologic parameters with poor prognostic and predictive power. There is an urgent need for enhanced biomarkers to guide therapy of this lethal disease. Here we have developed a genomic signature of bladder cancer progression using whole transcriptome profiling technology. Methods: 251 FFPE bladder cancer specimens were obtained from patients undergoing radical cystectomy at the University of Southern California (1998-2004). All patients had pT2-T4a,N0 urothelial carcinoma in the absence of pre-operative chemotherapy. Median follow-up was 5 years. RNA expression levels were measured with 1.4 million feature oligonucleotide microarrays. Patients were divided into a training set (2/3 of cohort) to develop a genomic classifier for risk of progression (defined as any type of bladder cancer recurrence), and a validation set (1/3 of cohort). In parallel, multivariable analysis was used to develop a clinical classifier using typical clinical and pathologic variables. Finally, a genomic-clinical classifier was built combining the genomic classifier with clinical variables using logistic regression. The receiver-operator characteristic (ROC) area under the curve (AUC) metric was used to evaluate each classifier in the validation set. Results: The genomic classifier consisted of 89 features corresponding to 80 genes that were combined in a k-nearest neighbor model (KNN89). KNN89 showed an AUC of 0.77 in ROC analysis on the validation set. The best clinical classifier showed an AUC of 0.72. The genomic-clinical classifier demonstrated an AUC of 0.81. Multivariable analysis incorporating all clinical parameters and KNN89 further revealed that KNN89 was the only significant predictor of bladder cancer progression (p=0.0077). Conclusions: We have developed a combined genomic-clinical classifier that shows improved performance over clinical models alone for prediction of progression after radical cystectomy. External validation of this classifier is ongoing.
VHL-mutant renal cell carcinomas contain cancer cells with mesenchymal phenotypes.
Authors: Gedye Craig , Sirskyj Danylo , Lobo Nazleen Carol , Evans Andrew , Fleshner Neil Eric , Robinette Michael , Zlotta Alexandre , Hamilton Robert , Kulkarni Girish S. , Finelli Antonio , Gallie Brenda L. , Jewett Michael A. S. , Ailles Laurie
Published: March 2020

4568

Background: To study “cancer stem cells” it is imperative to account for all stromal cell populations within the tumour. The existence of “cancer stem cells” in clear cell renal cell carcinoma (ccRCC) has not been examined in ex vivo patient samples. Methods: We established a multiplex flow cytometry (FC) antibody panel in ccRCC, which reliably identified stromal lineages including CD45+ immune, CD31+/CD144+ endothelial and fibroblast-marker-positive subpopulations, thus allowing isolation of "lineage-negative" tumor cells. To verify the identity of tumour-derived populations as either cancer cells or normal stromal cells, we took advantage of the fact that mutations in VHL occur early during ccRCC tumorigenesis and are found in two-thirds of patients. Results: We sequenced 18 patient tumor samples, 12 of which had VHL exome mutations. Targeted re-sequencing of FC sorted subpopulations from these patients’ samples revealed that while CD45+ immune cells and CD31+/CD144+ endothelial cells were genetically normal, a population of VHL-mutant fibroblast-marker positive cells was consistently identified in every patient’s tumour. Immunohistochemistry showed that fibroblast marker-positive VHL-mutant cells do not have the large “clear cell” morphology typical of the majority of the cancer cells in these tumours. When purified and cultured, these fibroblast marker-positive VHL-mutant cells proliferate extensively under mesenchymal culture conditions, but displayed different morphologies to lineage-negative VHL-mutant tumor cells. Functional characterization of these FC sorted cell subpopulations is ongoing, including proliferation, migration, invasion, differentiation and treatment resistance. Conclusions: The phenotype and preliminary functional characterization of these VHL-mutant fibroblast-marker positive cells suggests a mesenchymal differentiation program in ccRCC, with implications for the ontogeny, biology and clinical management of VHL-mutant renal cancer.
Pazopanib (P) and bevacizumab (B) in patients with metastatic renal cell carcinoma (mRCC) or other advanced refractory tumors: Phase I combination study final analysis.
Authors: Negrier Sylvie , Imbs Diane Charlotte , Pérol David , Bahleda Ratislav , Hollebecque Antoine , Boyle Helen Jane , Ferlay Celine , Metzger Severine , Blanc Ellen , Soria Jean-Charles , Escudier Bernard J. , Chatelut Etienne
Published: March 2020

4574

Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a recent VEGFR inhibitor P with B in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This double center trial was conducted with 3+3+3 escalation doses of P + B. The maximum tolerated dose (MTD) was the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. After preliminary DLT results, an approved by IDSMB extension cohort was enrolled and treated at MTD level.The effect of B on steady-state pharmacokinetic (PK) of P was also investigated by comparing PK at day 1 (D1) and D15 (day of B infusion). Results: 25 pts were enrolled with mRCC (n=7) or other advanced refractory solid tumors (n=18). Median age is 62 (41-79), 14 pts are male. At DL2 (n=10) 3 nephrectomized and 2 non-nephrectomized pts experienced DLT, as presented in the Table. In the 6-non-nephrectomized-pt extension cohort at DL1, 3 additional DLT were observed. Mean P AUC at D1 was higher than previously described in phase I P monotherapy (Clin Cancer Res 2009;15:4220). Mean P AUC at steady-state (D15) at both P dose levels was also significantly higher, though without being influenced by B infusion. Conclusions: The MTD of the P + B combination is respectively 400 mg/d and 7.5mg/kg (DL1) in all patients. Final PK analysis showed that there is no influence of B on P PK and that P AUC is higher than previously reported. Clinical trial information: NCT01202032. [Table: see text]
Impact of cytoreductive nephrectomy on disease-specific survival (DSS) in the cytokine and targeted therapy eras: Age- and TNM-stage matched analysis of SEER data.
Authors: Nelson Rebecca A. , Vogelzang Nicholas J. , Pal Sumanta Kumar
Published: March 2020

4579

Background: The role of cytoreductive nephrectomy (CN) for patients with mRCC was well-defined in the cytokine era. However, its role is controversial in the era of targeted therapies. Methods: The Survival, Epidemiology, and End Results (SEER) Database was queried to compare the relative benefit of CN in the cytokine era (defined as 1992-2004) as compared to the targeted therapy era (defined as 2005-2009). Patients with mRCC and clear cell, papillary or chromophobe histology were identified, and divided into cohorts with and without CN. Within each category, patients diagnosed during the cytokine era were matched by age and TNM stage to patients diagnosed during the targeted therapy era. Associations between clinicopathologic characteristics and DSS were explored through univariate and multivariate analyses. Results: Amongst matched pts who had received CN (n=2,218), no significant differences in age, gender, race, histology (clear cell v non-clear cell), T-stage, or N-stage were observed. Median DSS was superior in those patients diagnosed during the targeted therapy era as compared to the cytokine era (22 mos v 17 mos, P<0.0001). On multivariate analysis including the aforementioned clinicopathologic variables and DSS, diagnosis during the targeted therapy era was an independent predictor of improved survival amongst patients who had received CN (HR 0.78, 95%CI 0.70-0.87; P<0.0001). Amongst matched pts who had not received CN (n=4,214), there were no differences in clinicopathologic characteristics. Median DSS was similar in patients diagnosed during the targeted therapy era as compared to the cytokine era within this group (4 mos for each; P=NS). Conclusions: Patients who received CN during the targeted therapy era had a superior DSS as compared to patients who received the procedure during the cytokine era. In contrast, patients who had not received CN had a similar DSS across both time periods. While prospective trials mature (i.e., CARMENA and EORTC 30073), these data support the continued use of CN in the context of targeted agents.
Novel stratification of the recurrence risk following surgical extirpation of clear cell renal cell carcinoma using tissue biomarkers in the mammalian target of rapamycin pathway.
Authors: Krabbe Laura-Maria , Darwish Oussama M , Raj Ganesh , Youssef Ramy F. , Kapur Payal , Bagrodia Aditya , Belsante Michael , Lotan Yair , Margulis Vitaly
Published: March 2020

4581

Background: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway promotes invasiveness and metastatic potential in a variety of malignancies. The aim of the present study was to evaluate the association of altered expression of mTOR pathway components with recurrence outcome in non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Methods: Immunohistochemistry for phos-S6, phos-mTOR, mTOR, phos-AKT, HIF-1α, RAPTOR, PTEN, PI3K, and phos-4EBP1 was performed on tissue microarrays of patients treated for non-metastatic kidney cancer between 1997-2010. Patients were defined as having a low (<) or high risk (≥) of nomogram predicted recurrence (2001 MSKCC RCC post-op) using an 8% cutoff. The relationship between individual marker expression, as well as combined marker score (low, intermediate and high defined as ≤ 3, 4-5, >5 altered biomarkers; respectively) with the actual and predicted relapse rates was assessed. Results: The study included 419 non- metastatic ccRCC patients (pT1-T2 79.5%, pT3-T4 20.5%, Fuhrman nuclear grade 1-2 in 69%, 3-4 in 31%). 219 and 200 patients had low (<8%) and high (≥8%) nomogram-predicted 5-year risk of recurrence respectively. With a median follow-up of 2.2 years, recurrences were detected in 5 (2.3%) of the predicted low risk and 30 (15%) of the predicted high risk patients. mTOR pathway biomarker profiles were not predictive for patients at low predicted risk of recurrences. For patients at high predicted risk of recurrence, low, intermediate and high combined marker scores were found in 84 (42%), 79 (39.5%), and 37 (18.5%), respectively. The actual rates of recurrence were noted for 8.3% of low, 13.9% of intermediate and 32.4% of high combined marker score in a statistically significant distribution (p=0.027). Conclusions: The cumulative number of aberrantly expressed mTOR biomarkers correlates with a higher rate of recurrence. The combined marker score may help further stratify patients with high nomogram predicted risk of recurrence. Our data supports prospective evaluation of these biomarkers to augment current clinico-pathologic predictors of outcomes in ccRCC.
An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort.
Authors: Scher Howard I. , Smith Matthew R. , Sweeney Christopher , Corn Paul Gettys , Logothetis Christopher , Vogelzang Nicholas J. , Smith David C. , Hussain Maha , George Daniel J. , De Bono Johann Sebastian , Higano Celestia S. , Small Eric Jay , Goldin Jonathan , Brown Matthew S. , Aftab Dana T. , Noursalehi Mojtaba , Weitzman Aaron , Basch Ethan M.
Published: March 2020

5026

Background: The results of 144 pts with metastatic CRPC treated in a phase II NRE cohort with daily cabo 100 mg and 40 mg starting doses have been previously reported. Substantial rates of bone scan improvement, reductions in CTC counts and pain relief were observed. To better understand the implication of these effects, the association with OS was explored. Methods: Relevant baseline variables (LDH, BSLA, visceral disease, pain, hemoglobin, CTCs) and post-treatment changes at week 6: ≥30% reduction in BSLA using computer-aided assessment, CTC conversion (>5 vs. 4 or less/7.5 ml of blood), and pain intensity (7 day averaged worst pain score; BPI scale; using an IVR system) were associated with OS in 144 CRPC pts with bone metastasis who progressed within 6 months of docetaxel (D) treatment (≥225 mg/m2) in either bone or soft tissue. Median OS was compared between responders and non-responders for each of the above outcomes categories using a Cox proportional hazard model. The findings were examined further after adjusting for significant baseline covariates selected from a stepwise Cox regression model. Results: See Table. Conclusions: Recognizing the limitations of associating response with survival, this retrospective analysis of decreases in BSLA, CTC conversions and reductions in pain intensity support further study in ongoing phase III trials. Clinical trial information: NCT00940225. [Table: see text]
Genomic heterogeneity of circulating tumor cells in castration-resistant prostate cancer (CRPC) revealed by single-cell sequencing.
Authors: Welsh Allison , Danila Daniel Costin , Anand Aseem , Kendall Jude , Sawyers Charles L. , Fleisher Martin , Wigler Michael , Hicks James B , Scher Howard I.
Published: March 2020

5030

Background: Circulating tumor cells (CTC) provide an opportunity to sample multiple metastatic tumor sites through a single blood draw – a ”fluid biopsy.” NextGen DNA sequencing provides the means to obtain detailed genetic information from captured cells prior to and during treatment. Here we demonstrate the use of DNA sequencing to interrogate genome-wide copy number variations (CNV) at the single-cell level in CTC isolated from pts with CRPC. Methods: Pre- and post-treatment blood samples were obtained from pts treated at MSKCC. EpCAM+ events were collected singly and in groups by cytometric flow sorting and were subjected to DNA amplification and Illumina NextGeneration sequencing. Parallel samples were assayed using the Veridex CellSearch method to ensure the presence of malignant cells. Results: Samples with up to 50 EpCAM+ events analyzed in bulk displayed CNV patterns expected from published CRPC data. Subsequent single cell analyses showed that the method could reliably detect common genomic markers in CRPC, including AR amplification, PTEN and RB1 loss, and the TMPRSS-ERG fusion. Individual genomic CNV profiles obtained from 125 single cells isolated from 15 patients were then analyzed. Using unsupervised clustering, cells from each pt showed a closely related lineage structure, consistent with an evolution from a common ancestor. The degree of genomic heterogeneity within CTC from an individual pt was highly variable, with R2 correlation coefficients ranging from >0.92 (nearly homogeneous) to <0.75 (mixed populations). Two pts harbored separate subpopulations with both amplified AR and non-amplified AR cells and another displayed mixtures of genetic markers that changed over the course of treatment. Conclusions: The observed variation in complexity of CTC populations in CRPC pts underscores the importance of being able to sample and analyze multiple cells from an individual pt on multiple occasions and with real time analytics. Doing so is essential to understand and identify mechanisms of resistance so that they can be targeted effectively. Supported by STARR Cancer Consortium, NCI SPORE in Prostate Cancer; Department of Defense; Prostate Cancer Foundation.
Prostate-specific mRNA detection in whole blood as an analytically validated prognostic biomarker for patients with castration-resistant prostate cancer (CRPC).
Authors: Anand Aseem , Danila Daniel Costin , Heller Glenn , Herkal Amrita , Patel Chintan , Khanin Raya , Schultz Nikolaus , Lilja Hans , Fleisher Martin , Scher Howard I.
Published: March 2020

5032

Background: Detection of prostate-specific transcripts in blood has been associated with survival, but validated assays are lacking. We analytically validated a qPCR-based assay in CLIA environment to detect prostate cancer enhanced transcripts in whole blood and determine its prognostic significance relative to circulating tumor cell (CTC) enumeration. Methods: Blood was collected from patients with progressive CRPC in PAXgene tubes for total RNA extraction. Five genes overexpressed in prostate tissue, KLK3, KLK2, HOXB13, GRHL2, and FOXA1, were analyzed by RT-qPCR. Each qPCR-reaction was performed in 6 replicates and detection thresholds for each gene were chosen by receiver operator curve analysis. Detection rates were compared to enumeration using CellSearch in an independent data set of 97 CRPC patients and survival associations explored by concordance probability estimate (CPE). Results: Two or more genes were detected by qPCR in 53% (51 of 97, 95% CI 43-63%) of patients, and unfavorable CTC counts (≥5cells) were seen in 46% (45 of 97, 95% CI 36–56%). Transcripts were detectable in 21% (11 of 52, 95% CI 8–35%) of patients with favorable CTC counts (≤4). Similar to CTC enumeration, transcript detection predicted overall survival in a proportional hazards model. The predictive accuracy of qPCR detection in combination with CTC enumeration had a CPE of 0.752 (SE=0.038). Conclusions: This validated RT-qPCR assay detects prostate-specific mRNA in whole blood in more patients than CellSearch, is prognostic for survival, and may assess patient risk in conjunction with CTC enumeration. Its clinical utility will be prospectively explored. Supported by NCI SPORE in Prostate Cancer (P50 CA92629); the Department of Defense Prostate Cancer Research Program; Prostate Cancer Foundation; Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center; DoD Prostate Cancer Research Program Physician Research Award W81XWH-09-1-0307.
Validation of a genomic classifier that predicts metastatic disease progression in men with biochemical recurrence post radical prostatectomy.
Authors: Ross Ashley E. , Ghadessi Mercedeh , Davicioni Elai , Crisan Anamaria , Buerki Christine , Erho Nicholas , Mitra Anirban Pradip , Thompson Darby J. S. , Triche Timothy J. , Feng Felix Yi-Chung , Schaeffer Edward M.
Published: March 2020

5033

Background: Almost 50,000 men per year will present with biochemical recurrence (BCR) following local treatment for prostate cancer. These men with rising PSAs as the lone indicator of recurrence present a management dilemma due to their varied outcomes with only a proportion developing subsequent metastatic disease. Thus, there is a clear need to improve patient risk stratification in this context. Here, we evaluate Decipher, a genomic classifier (GC) in men with BCR following radical prostatectomy (RP) for its ability to predict metastasis. Methods: The 22-marker GC was validated in a prospectively designed case-cohort study of 1,010 clinically high-risk RP patients. 219 patients, including 85 who developed BCR at least 6 months post-RP were subjected to microarray analysis and GC scores were generated. Survival ROC curves, weighted Cox proportional hazards, and decision curves were used to compare the performance of the GC to Gleason score (GS), PSA doubling time (PSAdT) and time to BCR (ttBCR). Results: GC scores significantly stratified these men into those who would or would not develop metastasis after BCR (8% versus 40% of patients developed metastasis at 3 years following BCR depending on GC score category, p<0.001). The AUC for GC was 0.82 (95% CI, 0.76-0.86), compared to that of GS 0.64 (0.58-0.70), PSAdT 0.69 (0.61-0.77) and ttBCR 0.52 (0.46-0.59). In decision curve analysis, the GC had the highest overall ‘net benefit’ and in multivariable modeling with clinicopathologic variables, only GC (p=0.006) and GS (p=0.046) scores were significant predictors of metastasis. Conclusions: When compared to clinicopathologic variables, the GC better predicted metastatic progression among men with BCR following RP. While confirmatory studies in additional patient populations are required, these results suggest that use of the GC can allow for better selection of men requiring additional treatment at the time of BCR.
Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).
Authors: Saad Fred , Fizazi Karim , Smith Matthew R. , Griffin Thomas W. , Londhe Anil , Rathkopf Dana E. , Molina Arturo , Ryan Charles J.
Published: March 2020

5037

Background: BTT can delay symptomatic progression in cancer pts with bone metastases. In a post hoc analysis, we assessed the impact of concomitant BTT on outcomes in a recent large, multinational study in mCRPC pts without prior ctx. Methods: COU-AA-302 was a phase III trial in asymptomatic/mildly symptomatic pts with progressive mCRPC and no prior ctx. 1,088 pts were stratified by ECOG performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1 g or placebo QD, plus prednisone 5 mg BID. Radiographic progression-free survival (rPFS) and overall survival (OS) were primary end points; secondary end points were times to opiate use, ctx, ECOG-PS deterioration, and PSA progression. The effect of concomitant use of BTT on all end points was assessed retrospectively using a stratified Cox regression model with factors for treatment, concomitant BTT, interaction of treatment and BTT, and baseline covariates. All data were obtained from a prespecified interim analysis at 55% OS events. Results: Median follow-up at the time of analysis was 27.1 mos. Among intent-to-treat (ITT) pts, 184/546 AA and 169/542 P pts received concomitant BTT for treatment of bone metastases, either zoledronic acid (n = 330), other bisphosphonates (n = 16), denosumab (n = 22), and/or other BTT (n = 5). In these pts, concomitant BTT use was associated with improved OS, time to opiate use for cancer pain, and time to ECOG-PS deterioration (Table). Results were similar in a sensitivity analysis including only ITT pts with bone metastases at baseline. Conclusions: In this post hoc, exploratory analysis, concomitant BTT use was associated with delayed symptomatic progression in asymptomatic/mildly symptomatic mCRPC pts. This potential clinical benefit should be investigated in prospective studies. Clinical trial information: NCT00887198. [Table: see text]
First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide (LNA-ASO) to androgen receptor (AR) mRNA in patients with castration-resistant prostate cancer (CRPC).
Authors: Bianchini Diletta , Omlin Aurelius Gabriel , Pezaro Carmel Jo , Mukherji Deborah , Lorente Estelles David , Zivi Andrea , Ferraldeschi Roberta , Crespo Mateus , Buchbinder Aby , Attard Gerhardt , Scher Howard I. , De Bono Johann Sebastian , Danila Daniel Costin
Published: March 2020

5052

Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]
Interim safety results of a global early access protocol (EAP) of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after taxane-based chemotherapy.
Authors: George Daniel J. , McGowan Tracy , Daugaard Gedske , Flaig Thomas W. , Geczi Lajos , Hotte Sebastien J. , Mainwaring Paul N. , Saad Fred , Smith Matthew R. , Souza Ciro , Sternberg Cora N. , Tay Miah Hiang , Garrido Jose Manuel Tello , Londhe Anil , Naini Vahid , Todd Mary Beth , Molina Arturo
Published: March 2020

5059

Background: The COU-AA-301 phase 3 trial showed significantly longer overall survival for AA + prednisone (P) than P alone in mCRPC pts refractory to docetaxel. This global EAP was conducted in the same setting to collect additional safety data. Methods: Open-label EAP in pts with mCRPC who progressed after 1 - 2 chemotherapy regimens (≥ 1 taxane), resided in areas where AA was unavailable and were ineligible for ongoing clinical trials of AA. Pts received AA (1000 mg PO/d) plus P (5 mg bid) in 28 d cycles until disease progression. Only serious or clinically important adverse events (AEs) were to be reported by investigators. First interim results (clinical cut-off date: December 31, 2011), reported as part of regulatory submissions, are presented. Results: 1079 pts from 15 countries were included: N. America (47%), Europe (29%), Australia (13%), Latin America (7%), and Asia (3%). Median age: 70 years (range: 47 – 93); 89% of pts were White. Median treatment exposure, incl. pts still on treatment (285 pts), was ≈ 3 months. 620 pts (58%) received ≥ 4 treatment cycles, 58 pts (5%) received ≥ 8 cycles. 441 pts (41%) reported serious or clinically important AEs, which were treatment-related in 154 pts (14%). Most common grade 3-4 AEs: ↑ALP (6%), anemia (3%), hypertension (3%), back pain (2%), and fatigue (2%). Grade 3-4 AEs of special interest were infrequent: LFT abnormalities (8%), hypertension (3%), cardiac disorders (2%), hypokalemia (< 1%), fluid retention/edema (< 1%), osteoporotic fractures (< 1%). Main reason for discontinuation (795 pts): disease progression, in 335 pts (31%). 253 pts (23%) discontinued after marketing authorization. Discontinuations due to treatment-emergent AEs, death, or withdrawal of consent were < 6% each. Conclusions: The safety profile observed in these EAP interim results was consistent with that in the COU-AA-301 randomized, placebo controlled trial conducted in the same clinical setting. No new safety signals with AA plus P were detected in this expanded patient population, which included pts from Latin America and Asia, i.e. regions that did not participate in COU-AA-301. Clinical trial information: NCT01217697.
Identifying clinically relevant prognostic subgroups in node-positive postmenopausal HR+ early breast cancer patients treated with endocrine therapy: A combined analysis of 2,485 patients from ABCSG-8 and ATAC using the PAM50 risk of recurrence (ROR) score and intrinsic subtype.
Authors: Gnant Michael , Dowsett Mitchell , Filipits Martin , Lopez-Knowles Elena , Greil Richard , Balic Marija , Cowens John W , Nielsen Torsten O. , Shaper Carl , Sestak Ivana , Fesl Christian , Cuzick Jack M. ,   Austrian Breast and Colorectal Cancer Study Group
Published: March 2020

506

Background: Most postmenopausal women with node positive HR+ EBC receive adjuvant chemotherapy. We hypothesized that a molecular-based characterization of residual risk after endocrine therapy using the ROR score and IS may identify node-positive patient subgroups with limited long-term recurrence risk after endocrine therapy better than clinical-pathological risk assessment by clinical treatment score (CTS) alone. Methods: Long-term follow-up and tissue samples were obtained from 2,485 postmenopausal HR+ patients from the ABCSG-8 (N=1,478) and transATAC (N=1,007) trials. The PAM50 test was conducted on RNA extracted from paraffin blocks using the NanoString nCounter Analysis system. The ability of ROR, IS and ROR-defined risk groups (ROR-RG) to add prognostic information to CTS was assessed by the likelihood ratio test in a prospectively defined analysis plan. Results: Patients in the combined data set were grouped by the number of positive nodes into 1 (N1), 2 (N2), or 2 or 3 (N2-3),Baseline hazards for these subgroups were similar in the two trials. ROR score, IS and ROR-RG added statistically significant prognostic information (10-year distant recurrence risk) beyond CTS in all groups. In patients with one positive node, the absolute 10-year risk of distant recurrence was 6.6% [95% CI: 3.3%-12.8%] in the PAM-50-low risk group (40% of patients) and 8.4 % [5.3%-13.3%] in the Luminal A subgroup (69% of patients). Conclusions: The results of this combined analysis demonstrate that a significant proportion of N1 EBC patients have very limited long term recurrence risk and suggest the same for some N2 patients. The PAM50 ROR score, IS and ROR-RG reliably provide additional prognostic information beyond CTS and may be useful in deciding which women with node-positive HR+ EBC can be spared adjuvant chemotherapy. [Table: see text]
Effects on androgen receptor nuclear import by docetaxel, cabazitaxel, abiraterone, and enzalutamide: Potential mechanism for cross-resistance in castration-resistant prostate cancer (CRPC).
Authors: van Soest Robert J. , van Royen Martin E. , de Morrée Ellen S. , Wiemer Erik A.C. , Mathijssen Ron H.J. , De Wit Ronald , van Weerden Wytske M.
Published: March 2020

5064

Background: Recent reports have suggested that paclitaxel and docetaxel, which exert their therapeutic activity primarily through inhibition of microtubule function and mitosis, also impair androgen receptor (AR) signaling. AR signaling is the key therapeutic target for the newly available agents abiraterone and enzalutamide. A recent study suggested impaired efficacy of docetaxel when given after progression on abiraterone in patients with CRPC. To identify potential mechanisms of cross-resistance, we investigated whether and to what extent AR nuclear translocation is affected by docetaxel, cabazitaxel, abiraterone and enzalutamide. Methods: Hep3B cells stably expressing GFP labeled AR were used for AR translocation studies. Cells were seeded on a cover slip in steroid-stripped medium (DCC) and treated with docetaxel (1 µM), cabazitaxel (1 µM), abiraterone (6 µM) and enzalutamide (1 µM). The anthracenedione mitoxantrone (100 nM) that does not target the microtubule cytoskeleton was used as a control cytotoxic agent. Following incubation for 48 hours, the synthetic androgen R1881 was added to study dynamics of AR nuclear import by time-lapse confocal microscopy. Results: Docetaxel and cabazitaxel inhibited R1881 induced AR nuclear translocation with 21% and 34% respectively compared to control, while mitoxantrone did not affect AR transport. Abiraterone inhibited AR translocation with 58% and enzalutamide completely blocked AR translocation. Conclusions: These data point towards a role for microtubules in AR nuclear transport and an additional mechanism of taxane activity in CRPC. Docetaxel, cabazitaxel, abiraterone and enzalutamide all interfere with AR nuclear transport, which is a crucial step in AR signaling. Our findings identify and provide insight in a potential mechanism of clinical cross-resistance between the two taxanes currently registered for treatment in CRPC and the novel agents abiraterone and enzalutamide. Further investigations are warranted in order to define if this potential cross-resistance impacts the most suitable treatment sequence for these drugs in CRPC.
Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.
Authors: Loriot Yohann , Fizazi Karim , De Bono Johann Sebastian , Forer David , Hirmand Mohammad , Scher Howard I.
Published: March 2020

5065

Background: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The phase III AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months (P <0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367:1187). Here we assess the effect of ENZA on outcomes in pts with liver or lung metastases in the AFFIRM trial. Methods: The AFFIRM trial was a phase III multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/day or PBO, stratified by baseline ECOG and mean pain score. The primary endpoint was overall survival (OS). Radiographic progression-free survival (rPFS) was a key secondary endpoint. PSA response defined as a decline of ≥50% compared to baseline, and soft tissue objective response per RECIST 1.1 were also assessed and reported here. Results: Pts with liver mCRPC comprised 11.5% (92/800) of ENZA pts and 8.5% (34/399) of PBO pts. Pts with lung mCRPC comprised 15.3% (122/800) of ENZA pts and 14.8% (59/399) of PBO pts. The median OS for patients with liver and/or lung mCRPC in the AFFIRM trial was 11.4 months (ENZA: 13.4 months; PBO: 9.5 months). Improved outcomes with ENZA treatment were observed in both liver and lung mCRPC pts. Conclusions: In the phase III AFFIRM trial, pts with lung mCRPC had higher median OS than pts with liver mCRPC. ENZA resulted in higher response rates in both liver and lung mCRPC pts. OS and rPFS were also improved in both pt groups treated with ENZA. Clinical trial information: NCT00974311. [Table: see text]
Prognostic impact of the 21-gene recurrence score in patients presenting with stage IV breast cancer.
Authors: King Tari A. , Lyman Jaclyn P , Gonen Mithat , Voci Amy , De Brot Marina , Boafa Camilla , Sing Amy Pratt , Hwang Eun-Sil Shelley , Alvarado Michael , Liu Minetta C. , Boughey Judy Caroline , McGuire Kandace P. , Van Poznak Catherine H. , Jacobs Lisa K. , Meszoely Ingrid M. , Krontiras Helen , Babiera Gildy , Norton Larry , Morrow Monica , Hudis Clifford ,   Translational Breast Cancer Research Consortium
Published: March 2020

507

Background: The 21-gene Recurrence Score (OncotypeDX Breast Cancer Assay) predicts outcome and benefit from chemotherapy (CT) in early stage ER+ BC treated with adjuvant endocrine therapy. We evaluated the association between Recurrence Score (RS), time to progression (TTP), and overall survival (OS) in patients with stage IV BC enrolled in TBCRC 013. Methods: TBCRC 013 is a registry study evaluating surgery of the primary tumor in pts presenting with Stage IV BC. From 7/09 - 4/12, 128 evaluable pts were enrolled in two cohorts (A: metastases (mets) with intact primary tumor (n=112); B: mets within 3 months of primary surgery (n=16)). This study includes 110 pts with pre-treatment primary tumor samples available for analysis. Clinical variables, TTP and OS were correlated with RS using long-rank, Kaplan-Meier and Cox regression. Results: Median pt age was 52yrs (21-79) and median tumor size 3.1cm (0.7-15). 82 (80%) were ER+, 83 (81%) Her2(-) and 51 (46%) had bone-only mets. Cohorts A and B did not differ. At a median follow-up of 26 mos (1-47), median TTP is 19 mos (95%CI16-25) and surgery is not associated with OS. 102 samples qualified for RS. 23 (23%) had low RS<18, 29 (28%) intermediate RS, 18-30; and 50 (49%) high RS≥31. Age, tumor size or site of 1stmets was not associated with RS. Risk groups were prognostic for TTP in ER+ pts and for 2 yr OS in ER+Her2- pts (Table). In Cox models continuous RS was also prognostic for TTP in ER+ pts (HR 3.5; for 50 point difference (PD) 95%CI 1.5-8.1, p=0.003) and for OS in ER+Her2- pts (HR 21.4, for 50 PD 95%CI 2.2-204.4, p=0.008). In MVA, adjusting for clinical variables, RS remained prognostic for TTP in ER+ pts (p=0.01). Further analysis of surgery in this trial is ongoing. Conclusions: The 21-gene RS is independently prognostic for TTP in ER+ Stage IV BC. RS is also prognostic for OS in ER+Her2- BC, suggesting that a high RS may be a surrogate for endocrine resistance and could be used to select pts with ER+ Stage IV BC for CT. A randomized trial to address this hypothesis is warranted. Clinical trial information: NCT00941759. [Table: see text]
The impact of reducing the frequency of prostate specific antigen (PSA) testing among men on active surveillance for prostate cancer.
Authors: Cooperberg Matthew R. , Newcomb Lisa F. , Brown Elissa C. , Zhao Shanshan , Feng Ziding , Brooks James D. , Lin Daniel W ,   Canary PASS Investigators
Published: March 2020

5092

Background: Active surveillance is a management strategy for men with low risk prostate cancer. Most surveillance regimens include routine PSA assessments, typically performed q 3 mos, although recent studies have questioned the utility of short-term PSA kinetics. Moreover, frequent PSA assessments may be associated with repeated intervals of anxiety around the time of testing, decreasing overall quality of life and potentially leading to avoidable interventions. We hypothesized that PSA assessment q 6 mos rather than q 3 mos would yield similar PSA kinetics calculations. Methods: We analyzed data from the Prostate Active Surveillance Study (PASS), a prospective, multicenter cohort accruing data and biospecimens from men on surveillance at 9 sites across North America. In PASS, PSAs are measured q 3 mos, with high completeness of data. We included data from men who had at least 5 PSA assessments after diagnosis, separated by ≥6 months (most had 10 PSAs separated by 3 months). PSA doubling time (PSADT) was calculated as ln(2) divided by the slope of a regression line drawn through the 5 PSAs. PSADT3 and PSADT6 were defined as the PSADT calculated from q 3 mos and q 6 mos data, respectively; for PSADT6, PSAs between each 6-month measurement were ignored. In each case, PSADT of 0-3 years defined progression, and PSADT > 3 years or declining PSA defined non-progression. Results: 161 men had sufficient PSA followup for analysis. 133 had no progression by either PSADT3 or PSADT6, and 16 progressed by both PSADT calculations. 4 and 8 men, respectively, progressed only by the PSADT3 or PSADT6 calculation but not by the other calculation. The κ score for agreement of progression ascertainment between PSADT3 and PSADT6 was 0.68, and McNemar’s test indicated no statistically significant difference between the two assessments (p=0.39). Conclusions: Calculating PSADT using 6-month rather than 3-month PSA assessments does not significantly change ascertainment of PSA progression in men on surveillance. Our finding suggests that surveillance protocols may reduce the frequency of PSA testing, potentially reducing unnecessary biopsy procedures and patient anxiety due to more frequent PSA measurements.
A phase II randomized trial of lapatinib with either vinorelbine or capecitabine as first- and second-line therapy for HER2 overexpressing metastatic breast cancer (MBC).
Authors: Papadimitriou Christos A. , Sarosiek Tomasz , Pikiel Joanna , Karaszewska Boguslawa , Salat Christoph , Caglevic Christian , Potemski Piotr , Brain Etienne , Briggs Kathryn Jane , DeSilvio Michelle , Marini Luca , Janni Wolfgang
Published: March 2020

516

Background: Lapatinib (L) is approved for the treatment of human epidermal growth factor receptor 2 (HER2) positive MBC in combination with capecitabine (C) following progression after trastuzumab, anthracyclines and taxanes. Vinorelbine (V) is an important chemotherapy option in MBC. This randomized, open-label, multicenter phase II study (NCT01013740) evaluated the efficacy and safety of L with either V or C in women with HER2+ MBC. The analysis of progression-free survival (PFS) and safety showed comparable rates of efficacy and tolerability between the 2 arms (Janni et al, SABCS 2012). Here we report the results of the overall survival (OS) and crossover analyses. Methods: Patients with MBC who had received ≤1 chemotherapy regimen in the metastatic setting were randomized 2:1 to either L 1250 mg orally once daily (QD) continuously + V 20 mg/m2 intravenously on days 1 and 8, every 3 weeks, or L 1250 mg orally QD continuously + C 2000 mg/m2/day orally in 2 doses, 12 hours apart on days 1-14 every 3 weeks. Patients were stratified by prior receipt of therapy for MBC and site of metastatic disease. The primary endpoint was PFS. Other endpoints included OS, overall response rate and safety. Patients progressing on one treatment arm were given the option of crossover to the other arm. All analyses were conducted with a descriptive intent only. The control arm of L+C was included in the study design to validate the patient population and lend support to the activity of L+V. Results: 112 patients were randomized in the study; 37 to the L+C arm and 75 to the L+V arm. The median OS in the L+C arm was 19.4 months [95% CI: 16.4-27.2] and 24.3 months [95% CI: 16.4-NE] in the L+V arm. At the time of analysis 42 patients had crossed over; 29 patients to L+C and 13 to L+V. Median PFS after crossover was 4 months [95% CI: 2.1-5.8] in the L+C arm and 3.2 months [95% CI: 1.7-5.1] in the L+V arm. Conclusions: L+V has shown consistent median OS with that reported in the pivotal study of L+C. The exploratory analysis of patients retreated with L after progression on L supports the biological rationale for maintaining HER2 suppression in HER2+ patients with progression on prior lines of anti-HER2 agents. Clinical trial information: NCT01013740.
The relationship between quantitative HER2 gene expression by the 21-gene RT-PCR assay and adjuvant trastuzumab (H) benefit in NCCTG (Alliance) N9831.
Authors: Perez Edith A. , Butler Steven M , Dueck Amylou C. , Baehner Frederick L. , Jamshidian Farid , Cherbavaz Diana B. , Thompson E Aubrey , Shak Steven , Kaufman Peter Andrew , Davidson Nancy E. , Gralow Julie , Asmann Yan W , Ballman Karla V.
Published: March 2020

520

Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg<10.7, equiv 10.7 to <11.5, and pos ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (>10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]
Combination trastuzumab and chemotherapy to induce immunity to multiple tumor antigens in patients with HER2-positive metastatic breast cancer: NCCTG (Alliance) studies N0337 and N98-32-52.
Authors: Clynes Raphael , Knutson Keith L. , Ballman Karla V. , Erskine Courtney L. , Norton Nadine , Sumrall Susan V. , Northfelt Donald W. , Tan Winston , Calfa Carmen Julia , Pegram Mark D. , Perez Edith A.
Published: March 2020

521

Background: The addition of trastuzumab to chemotherapy improves responses to therapy and extends survival among patients with metastatic HER2 breast cancer. Several mechanisms have been proposed for the activity of this combination therapy. Trastuzumab, specifically, is thought to activate NK cells and blunt HER2 signaling. Prior work from us has shown that combination trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy. Despite that, it remains unclear whether the immunity that was induced was due to complexing of non-tumor derived HER2 or antigen derived from the tumor site. In the present work, we addressed this question by assessing if combination therapy induced epitope spreading to tumor antigens other than HER2. Methods: Pre-and post-treatment sera were obtained from 56 women enrolled in 2 NCCTG clinical trials, N0337 and 98-32-52. IgG antibodies to HER2 intracellular domain (HER2), p53, IGFBP2, CEA and tetanus toxoid (TT) were examined using ELISAs. Sera from an age-matched group (N=56) of controls and 12 patients treated in the adjuvant setting were also examined. Results: Prior to therapy, metastatic patients had higher IgG levels (≥ 2-fold) to p53 and HER2 but not CEA, IGFBP2 and TT, relative to the controls. Similarly, adjuvant patients had elevated IgGs to multiple tumor antigens prior to therapy, relative to controls. Following therapy, levels of IgG to IGFBP2, HER2, and p53 increased in 81% of metastatic patients, with mean increases of 3.2 (±0.6 sem), 6.2 (±2.7) and 2.7 (±0.7) fold, respectively (p<0.05). Levels of antibodies to TT and CEA were not elevated by treatment. In contrast, IgGs were not increased in adjuvant patients; consistent with the idea that immunity depends on the presence of threshold levels of antigens. Conclusions: These results show that combination treatment induces adaptive immunity to antigens released by tumor and that metastatic patients remain capable of responding immunologically to their cancer. Thus, in metastatic breast cancer patients, combination trastuzumab and chemotherapy may behave as a vaccine.