bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC).
Authors: Wiechno Pawel J. , Chlosta Piotr , Pikiel Joanna , Somer Bradley G. , Mellado Begoña , Duran Martinez Ignacio , Castellano Daniel E. , Wedel Steffen , Cervera Grau Jose Manuel , Callies Sophie , Andre Valerie , Brown Jacqueline , Hurt Karla , Lahn Michael M. F. , Stöckle Michael , Reuter Christoph , Heinrich Bernhard
Published: March 2020

5019

Background: In prostate cancer, expression of survivin, a protein that inhibits apoptosis, is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination. Methods: Adult patients (pts) with CRPC, ECOG performance status <2, and no bone or CNSmetastases were randomized 1:2 to standard docetaxel/prednisone every 21 days (Arm A) or standard therapy combined with LY2181308 given as a 3-hr IV infusion (Arm B). Analysis was planned and performed after 130 pts progressed or died. This assessment provided a 70% chance of detecting a difference in progression-free survival (PFS) at the 10% significance level. Initially, LY2181308 was given as a loading dose (3 consecutive days) and then as a weekly 3-hr IV maintenance dose. Arm B also included a window treatment with LY2181308 monotherapy equivalent to a 21-day cycle of docetaxel before starting combined treatment. The primary endpoint was PFS. Results: This study enrolled 154 pts. The median PFS for Arm B was 8.64 (90% CI, 7.39–10.45) months vs. 9.00 (90% CI, 7.00–10.09) months in Arm A, showing no statistical difference (log rank p=0.755). The median overall survival (OS) for Arm B was 27.04 (90% CI, 19.94–33.41) months vs. 29.04 (90% CI, 20.11–39.26) months for Arm A (log-rank p= 0.838). The PSA responses (>50% reduction in PSA) were similar: 56.9% for Arm A and 56.1% in Arm B (p=0.856). Most pts had no pain or mild pain at baseline and during the active period. Pts treated in Arm B had a higher frequency of serious and nonserious adverse events (AEs) than those in Arm A. The observed AE and pharmacokinetic (PK) profiles were consistent with the known safety and PK profiles of LY2181308 and docetaxel. Conclusions: The addition of LY2181308 to a standard docetaxel/prednisone regimen showed no improvement in PFS, PSA response, and OS in first line CRPC pts. The safety profile of docetaxel and LY2181308 is predictable and consistent with the known safety profiles. Clinical trial information: NCT00642018.
The genomic relationship among matched prostate cancer foci.
Authors: VanderWeele David James , Brown Christopher D. , Grossman Robert L. , Taxy Jerome B. , Stadler Walter Michael , White Kevin P.
Published: March 2020

5028

Background: Cancer management is influenced by how one views progression and how one calculates the risk of metastases and death. For prostate cancer, this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. Despite recommendations supporting active surveillance for Gleason 6 prostate cancer, the vast majority of American patients receive aggressive local therapy, in part based on a presumption that low grade cancer progresses to high grade, lethal disease. Methods: To assess the genomic relationship between low and high grade disease, laser capture microdissection was used to isolate concurrent cancer foci from prostates with multifocal disease, and somatic mutations were identified using exome sequencing. The relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects, and a lymph node metastasis was examined for two of those subjects. Results: We obtained an average of 41-fold median coverage of the exome, with an average high confidence mutation rate of 0.8/Mb. Seventy of 79 (0.886) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 15 of 80 (0.188) high confidence somatic mutations in the high grade focus were private. Seven of the 80 (0.088) were shared with low grade foci, and 65 (0.813) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations is consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.
The ELDORADO study: A phase II randomised study of concurrent weekly docetaxel, IMRT, and ltadt in patients with high-risk prostate cancer.
Authors: Wilke Derek , Wood Lori , Walker Heather , Bell David , Rendon Ricardo A. , Hollenhorst Helmut , Rutledge Robert , Bowes David , Robar James , Drucker Arik Marc , Cwajna Slawa , Bailly Greg , Ago Tetteh
Published: March 2020

5048

Background: Treatment intensification is warranted for ‘high risk’ prostate cancer. Docetaxel (DO) and radiotherapy (IMRT) may cause dose-limiting GI or GU toxicity. Treating the whole pelvis last (WP-L) versus the whole pelvic lymphatics first (WP-F) could reduce the number of dose delays or omissions of DO. Methods: We performed a double-blind, randomized trial, in patients with ‘high risk’ non-metastatic prostate cancer who had any one of the following: 1) ≥ T2c TNM category, 2) Gleason score ≥ 8, or PSA > 20 and < 50 µg/L, OR have a greater than 50% risk of recurrence after radical prostatectomy (RP), as predicted by the Kattan nomogram, with no evidence of metastatic disease. Patients receive long-term androgen deprivation therapy (LTADT), and after 4 months of neoadjuvant ADT, receive IMRT and concurrent DO 20 mg/m2 x 8 weekly infusions. Patients were randomized to receive WP-F followed by a boost to the prostate/prostate bed, or to have WP-L. The primary outcome was to compare the number of DO dose reductions, delays or omissions due to GI or GU toxicity, between arms. Target sample size was 86 patients (pts). Results: 98 pts were registered, 88 were randomized, 2 withdrew consent, leaving 42 pts randomized to WP-F, and 44 pts to WP-L. The trial was closed to accrual Feb 2, 2012. Twenty-five pts had previous RP (29%). Seven pts (16.6%) allocated to WP-F had chemotherapy dose reductions/delays versus 3 pts (6.8%) allocated to WP-L , which was not statistically significant (p=0.19). Overall 80.2% of pts received all 8 weekly doses of DO and IMRT (WP-F vs. WP-L: 78.6% vs.81.8%, p=0.9). Actuarial overall survival at 4 years is 96 % (WP-F vs. WP-L: 94% vs.97%, p=0.6). Biochemical relapse-free survival at 4 years is 96.7% (WP-F vs. WP-L: 98% vs.97%, p=0.92). Two patients have needed surgical intervention for Grade > 3 GU toxicity. Cumulative treatment-related grade 3 or 4 GI or GU toxicity was 36%. When patients were last seen, only 2/84 (2.3%) patients had ongoing grade 3 GI or GU toxicity at a median follow up of 2.7 years Conclusions: Concurrent use of DO and IMRT is feasible with reasonable toxicity. Sequence inversion does not enhance chemotherapy delivery. Clinical trial information: NCT00452556.
A phase I/II study of cabazitaxel (Cbz) combined with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed after docetaxel (D) chemotherapy: Preliminary results.
Authors: Massard Christophe , Pezaro Carmel , Bobilev Dmitri , Omlin Aurelius Gabriel , Bianchini Diletta , Lorente Estelles David , Albiges Laurence , Loriot Yohann , Varga Andrea , Nguyen Thi Xuan Quyen , Fizazi Karim , De Bono Johann Sebastian
Published: March 2020

5049^

Background: Both Cbz and AA have demonstrated significantly improved survival in randomized Ph 3 studies in pts with mCRPC and progressive disease after D treatment. Cbz and AA have established non-overlapping adverse event (AE) profiles. A Ph 1/2 study was initiated to investigate the combination of Cbz + AA for the treatment of mCRPC (NCT01511536). Methods: Pts with progressive mCRPC after D were enrolled. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + AA (Ph 1), and the PSA response rate (RR) with this combination (Ph 2). Secondary endpoints included AEs, pharmacokinetics (PK) and efficacy. All pts received oral AA 1000 mg QD and P 5 mg BID. In Ph 1, pts received 1 of 2 dose levels (DL) of Cbz (20 and 25 mg/m2 IV Q3W) according to a 3+3 design. A 2-cycle DLT observation period was used. Here, we report results of Ph 1. Results: Ten pts were enrolled in Ph 1; 9 were evaluable: 3 at DL1 and 6 at DL2 completed 2 cycles without DLTs (total number of cycles = 46). In general, AEs were Grade (Gr) 1/2; the most frequent all-Gr AEs by pt cycle were asthenia (39%), diarrhea (37%; Gr 3 in 1 pt), back pain (26%), nausea (20%), constipation (20%), anemia (17%), decreased appetite (17%) and fatigue (15%; Gr 3 in 2 pts). In the safety population, 0/3 pts at DL1 and 2/7 pts at DL2 experienced Gr 3–4 neutropenia. The MTD was established at the full approved doses of both drugs (Cbz 25 mg/m2/AA 1000 mg). In 6 pts evaluable for PK (DL1 and DL2), median Cbz clearance (coefficient of variation %) was similar at cycle 1 (Cbz alone: 28.9 L/h/m2 [11%]) and cycle 2 (Cbz + AA coadministration: 28.6 L/h/m2 [42%]). In 9 evaluable pts, 55% PSA RR was observed. Conclusions: In this Ph 1 study, Cbz in combination with AA appeared to have a manageable safety profile. Gr 3–4 neutropenia was observed in 2 of 10 patients. Daily AA treatment did not affect Cbz clearance; Cbz exposure was comparable to previous studies of Cbz + P treatment. The Ph 2 portion is ongoing at the established MTD. Detailed safety, PK and preliminary efficacy data (Ph 1) will be presented. Clinical trial information: NCT01511536.
Clinicopathologic features and clinical outcomes associated with Gleason upgrading from biopsy to radical prostatectomy.
Authors: Yoo Sun Mi , Werner Lillian , Nakabayashi Mari , Sweeney Christopher , Hirsch Michelle S. , Kantoff Philip W. , Pomerantz Mark M
Published: March 2020

5056

Background: Gleason score stratifies patients into prognostic categories and is critical in guiding treatment. Previous series indicate that ~25% of patients with low-grade (Gleason ≤6) disease on biopsy are upgraded to higher grade disease upon radical prostatectomy (RP). We sought to characterize the clinical and pathologic variables associated with upgrading and investigate its clinical implications. Methods: 1,469 prostate cancer patients underwent prostate biopsy and RP, were seen at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (DFCI/BWH), and had tissue specimens reviewed by DFCI/BWH genitourinary pathologists between 1999-2011. Associations between Gleason upgrading and clinical and pathologic variables were assessed using Wilcoxon’s non-parametric test and Fisher’s exact tests. Log rank test was used to assess association between upgrading and time to biochemical recurrence (BCR). Results: Of 1,469 patients, 958 (65%) had biopsy Gleason 6 and 511 (35%) had biopsy Gleason 7. Among individuals with biopsy Gleason 6, 336 (35%) were upgraded to Gleason ≥7 upon RP (275 3+4 and 49 4+3) while 622 (65%) remained Gleason 6 at RP. Variables associated with increased risk of upgrading: greater PSA at diagnosis (p=1x10-4); age >58 (OR=1.62, p < 1x10-4); >1/3 positive biopsy cores (OR=2.1 for 33-50% compared to ≤33%, p < 1x10-4). In this study the number of cores biopsied was not associated with upgrading. Gleason upgrading was also associated with extraprostatic tissue involvement (OR=1.69, p=0.005). Patients upgraded from biopsy Gleason ≤6 to Gleason 7 on RP had a longer time to BCR than those with Gleason 7 on both biopsy and RP, but a shorter time to BCR than those who remained Gleason 6 on RP (adjusted hazard ratio 0.69, 95% CI 0.49-0.98, p=0.03). Conclusions: Gleason upgrading from low-grade to higher grade disease is associated with a higher PSA at diagnosis, older age at diagnosis, and a greater number of positive biopsy cores. Clinically, prostate cancers upgraded from Gleason ≤6 to Gleason 7 appear to behave differently than those who are not upgraded. These results could have implications in determining ideal candidates for active surveillance.
Novel predictive markers of PSA response to abiraterone acetate in men with metastatic castration-resistant-prostate-cancer (mCRPC).
Authors: Leibowitz-Amit Raya , Templeton Arnoud J. , Atenafu Eshetu G. , Vera-Badillo Francisco Emilio , Chllamma Muralidharan , Solow Henry L. , Knox Jennifer J. , Tannock Ian , Sridhar Srikala S. , Joshua Anthony Michael
Published: March 2020

5058

Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC pre- and post- chemotherapy. To date, clinical predictive biomarkers of response remain poorly characterized. The aim of this retrospective study was to identify and analyze predictors of response to AA in men with mCRPC. Methods: All men receiving AA at the Princess Margaret Cancer Centre between November 2009 and December 2012 were reviewed. PSA response rate (RR) was defined according to PCWG2 criteria and assessed 12 weeks after AA start. Potential predictive factors were analyzed using uni- and multivariable logistic regression models. Results: In total, 70 patients were evaluable for response: 34 men were chemotherapy naive and had a PSA RR of 44% (95% CI 27-62%); 36 men had prior chemotherapy and had a PSA RR of 33% (95% CI 17-50%). In univariable analysis, pre-treatment lactate dehydrogenase (LDH) level >220 U/L (ULN) and a neutrophil-to-lymphocyte ratio (NLR) >5 were both significantly associated with a lack of PSA response. On multivariable analysis, NLR>5 remained significantly associated with lack of a PSA response (Table 1A). Men were then stratified into three groups according to these two variables. These groups were significantly associated with RRs (Table 1B). PSA RR was not found to be associated with the Gleason score, initial stage, time from initial diagnosis to mCRPC or to AA initiation, prior ketoconazole or docetaxel treatment, pre-treatment alkaline phosphate or PSA doubling time. Conclusions: A pretreatment NLR>5 and an LDH>ULN were both strongly associated with a lack of PSA response to AA. These factors may be key in stratifying men into different response groups to AA. [Table: see text]
Factors impacting decision by African American and underserved populations to choose active surveillance in early-stage prostate cancer.
Authors: Gillespie Theresa Wicklin , Petros John , Goodman Michael , Lipscomb Joseph , Britan Laura , Rowell Jessica Lauren , Herrel Lindsey Allison , Echt Katharina V
Published: March 2020

5067

Background: African-American (AA) men have the highest rates of prostate cancer (PCa) incidence and mortality in the U.S. Screening for PCa with prostate specific antigen (PSA) has allowed detection of early stage disease, but side effects of radical prostatectomy and radiation raise concerns about unfavorable risk:benefit ratios of PSA screening and subsequent therapy. Active surveillance (AS) is an option for early-stage PCa (ESPC), but only 10% of men eligible for AS choose this approach. The 2011 NIH State-of-the-Science Conference promoted the need to enhance decision-making (DM) about AS. In 2012, the U.S. Preventive Services Task Force recommended against PSA screening, while encouraging patient DM. Our study examined DM needs by men (N=204; 68% AA; screening PSA within normal limits) and their significant others (SO) (N=181; 65% AA) regarding AS and other ESPC options. Methods: This multi-center, mixed methods study (N=402; 51% rural) included 5 sites nationwide. Subjects completed quantitative questionnaires prior to focus groups (FG); 54 FG were held, with separate groups for men and SO. Results: After adjusting for education, comorbidities, insurance, age, health literacy, distance to treatment center, willingness to travel, income and numeracy score, AA men were significantly more likely to be influenced by convenience (OR: 2.84, 95% CI: 1.42-5.65) compared to Caucasians. Rural residence, however, did not affect DM. In qualitative analysis, numerous themes were identified relevant to choice of AS: physician treatment discussions being limited to their own specialty; confusion due to conflicting sources of information; convenience; worry about untreated cancer remaining and treatment toxicities; and lack of awareness of AS as an option. SO tended to value cure over avoiding side effects. Conclusions: While the impact of new PCa screening guidelines is uncertain, for AS to become a viable treatment option, providers will need to discuss along with other therapeutic alternatives. SO are influential in DM and may be less enthusiastic about AS than men. For AA men, AS may be a particularly attractive option given the relative influence of convenience in DM.
Risk of missing advanced stage or high grade tumors during active surveillance (AS) even in favorable-risk prostate cancer (PC).
Authors: Kim Jeri , Ward John Francis , Pettaway Curtis A. , Wang Xuemei , Kuban Deborah A. , Frank Steven J. , Lee Andrew , Pisters Louis L. , Matin Surena F. , Shah Jay Bakul , Karam Jose A. , Chapin Brian Francis , Papadopoulos John N. , Achim Mary F. , Hoffman Karen Elizabeth , Pugh Thomas J. , Choi Seungtaek , Logothetis Christopher , Troncoso Patricia , Davis John W.
Published: March 2020

5069

Background: Owing to tumor heterogeneity, no standard selection criteria exist among prospective AS cohorts. Generally, men with low-stage, -volume, and -grade PC and low prostate-specific antigen (PSA) are eligible. In our prospective single-institution AS trial, men with early-stage PC were stratified: Gr I (favorable risk), II (pt’s choice), or III [competing comorbidities prevent local therapy (Tx)]. We report our experience with Gr I. Methods: Eligibility for Gr I: Gleason score (GS) ≤6, 1 positive (pos) core (<3 mm), and PSA <4 ng/mL or GS 7 (3+4), 1 pos core (<2 mm), and PSA <4 ng/mL. Monitoring q6mo included PSA, testosterone, and digital rectal exam. All pts had repeat biopsy (re-BX) at 1 y and then on predetermined BX scheme. Later, re-BX was required within 6 mo of study entry per an 11-core BX scheme (also used during AS). Definitive Tx was offered to pts who met reclassification based on clinical, BX (upgrading, ↑ in pos core BX, and/or ↑ tumor length), and/or radiographic progression. Imaging studies [bone/CT scans, endorectal MRI (eMRI)] were at physician’s discretion. Results: From 2/2006 to 2/2012, 585 pts enrolled; 191 met Gr I criteria (41 before, 150 after re-BX requirement). Median age was 64 y (range, 36–83); 82% were white, 8% African-American, 8% Hispanic, 2% Asian; 4% had cT1a/cT1b, 84% cT1c, and 12% cT2 disease. Most (189/191) had GS 6 [1 had GS 5, and 1, GS 7 (3+4)]. Median PSA was 3.3 (range, 0.2–10). With median follow-up of 36.2 mo (95% CI: 30.6–41.7), 32/191 (17%) were reclassified [20/41 (49%) before and 12/150 (8%) after re-BX requirement]. Of 32 reclassified, 17 were due to GS: 11 to GS 7 (3+4), 4 to GS 7 (4+3), and 2 to GS 8 (4+4). Ten of the 32 reclassified chose Tx [4 radical prostatectomy (RP); 4 radiation; 2 cryotherapy]. RP showed a pT2N0 GS9 (4+5) apical tumor in 1 at 5 y, a pT3aN0 GS7 (4+3) tumor in 1 at 3 y, a pT2N0 GS7 (4+3) tumor in 1 at 1 y, and a T2N0 GS 7 (3+4) tumor in 1 at 2 y. Conclusions: Restrictive selection criteria and re-BX at study entry improve clinical risk classification; however, other improvements, including imaging and markers of disease progression could enhance pt selection for AS.
Final results of a phase II study of neoadjuvant metformin in prostatic carcinoma.
Authors: Joshua Anthony Michael , Zannella Vanessa E. , Downes Michelle R , Bowes Barbara , Koritzinsky Marianne , Sweet Joan , Trachtenberg John , Jewett Michael A. S. , Finelli Antonio , Fleshner Neil Eric , Pollak Michael N.
Published: March 2020

5070

Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who were found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that began treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 21 patients evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported during treatment or radical prostatectomy that were related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p<0.01) and waist/hip ratio (p<0.01). There was a trend for a PSA reduction (p=0.08). There were no correlations between any metabolic, morphometric or cancer-related serum indices. On a per patient analyses, metformin reduced a computerised relative ki67 proliferation index by an average of 29% (absolute difference of 1.4%) compared to the baseline biopsy (p=0.006). P-4eBP1 staining was also reduced as assessed by H-score (p<0.01) consistent with the ability of metformin to inhibit mTOR. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy and shows promising effects on proliferation and signaling indices. Further research is needed to define the clinical utility of metformin in prostate cancer. Clinical trial information: NCT00881725.
Association of SPARC expression with metastatic progression and prostate cancer-specific mortality after radical prostatectomy.
Authors: Jeldres Claudio , Johnston Richard Bruce , Porter Christopher R. , Nelson Peter
Published: March 2020

5071

Background: We assessed the expression of the glycoprotein SPARC (secreted protein, acidic, rich in cysteine) in patients with prostate cancer (PCa) treated with radical prostatectomy (RP) and studied its association with adverse clinico-pathological features at RP and long-term clinical outcomes, such as metastatic progression after surgery and cancer-specific death. Methods: Tissues from 78 patients with PCa were used to quantify SPARC expression using tissue microarray (TMA) and immunohistochemistry techniques (IHC). Anti-SPARC mouse monoclonal antibody were use to target the protein and for each patients 4 samples of tissue were used for cytoplasmic staining. Staining of each core was reviewed by an uropathologist who assigned a score (score 0-3) to each core and a global score also assigned to each patient (score 0-3). Analyses of the data relied in cross tables, T-test analyses, survival plots and Cox regression models. Results: Higher expression of SPARC protein was recorded in patients who develop metastases during follow-up after RP (p=0.025) and in patients who died of PCa after RP (p=0.002). Median follow-up of the cohort was 9.3 years after RP. At 5 years, 95.5%, 92.0% and 89.3% of patients were metastases-free for SPARC expression score 1, 2 and 3 respectively. For the same categories, 10 years after RP, 82.2%, 77.0% and 69.9% were metastases-free (Log-rank tests all p≤0.05). Similarly, patients with high SPARC expression had worse cancer-specific survival at 5 and 10 years after RP compared to those with low SPARC expression (Log-rank tests all p≤0.01 when score 1 was compared to score 2 or score 3). Finally, advanced stage at RP (T3-T4) [p=0.04] and high Gleason sum (8-10) [p=0.02] were also associated with higher expression of SPARC. Conclusions: High SPARC expression was associated with worse outcomes in men with prostate cancer treated with radical prostatectomy. Men who developed metastatic disease and men who succumbed to prostate cancer had higher levels of SPARC at radical prostatectomy than their counterpart. SPARC may have an important role in the progression of the disease and may eventually help clinician to better ascertain the risk of progression of the disease.
Quantifying copy number variations in cell-free DNA for potential clinical utility from a large prostate cancer cohort.
Authors: Schütz Ekkehard , Akbari Mohammad R , Beck Julia , Urnovitz Howard B. , Zhang William , Mitchell William M. , Nam Robert , Narod Steven
Published: March 2020

5072

Background: Prostate cancer (PrCa) is the most frequent non-dermatological malignancy in the male population. Genomic instability resulting in copy number variation (CNV) is a hallmark of malignant transformation. CNV traces from tumors in cell-free DNA (cfDNA) of prostate cancer patients may be identified through massive parallel sequencing (MPS) of serum DNA. These CNV traces may be biomarkers of cancer with clinical applications for screening and follow-up. Methods: DNA was extracted from serum of 205 PrCa patients (Gleason 2 to10), 207 age matched male controls (HC), 10 men with benign hyperplasia (BPH) and 10 with prostatitis (PiS). DNA was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on a SOLiD system and aligned to the human genome (Build 37). Hits were counted in sliding 100kbp intervals and normalized. Using a random-resampling procedure, genomic regions showing copy number variations in cfDNA that distinguish PrCa from HC were selected. A model using 20 cfDNA regions was cross-validated and used as cfDNA biomarker. Receiver operator characteristics (ROC) curves were calculated for assessment of diagnostic performance by means of area under the curve (AUC). Results: To assess whether CNVs in cfDNA are indicative of PrCa, the number of regions with significant CNV deviation was counted in a first subset of 82 PrCa. Using only the number of regions as measure resulted in an AUC of 0.81 (0.7 – 0.9, p<0.001). Therefore, all samples were used to select regions (n=80) in random resampling (50/50). These regions were used to define a highly significant 20-regions model using five rounds of 10-fold cross-validation (AUC: 0.85±0.7; p< 10-7). This final model discriminated between PrCa and HC with an AUC of 0.92 (0.87 – 0.95) reaching a calculated accuracy of 83%. Both BPH and PiS could be distinguished from PrCa using the cfDNA CNV biomarker with a predicted accuracy of 90%. Conclusions: MPS revealed that only a limited number of chromosomal regions showing CNVs are necessary to achieve statistical separation between prostate cancer and controls. This technique may prove to be clinically useful for screening and follow up of men with prostate cancer.
A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine versus capecitabine monotherapy in first-line HER2-negative metastatic breast cancer (MBC).
Authors: Goldstein Lori J. , Oliveira Celia Tosello , Heinrich Bernhard , Stemmer Salomon M. , Mala Carola , Kastner Sabine , Bevan Paul , Richters Lisa , Schmalfeldt Barbara , Harbeck Nadia
Published: March 2020

508

Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. uPA and PAI-1 are biomarkers validated at highest level of evidence in breast tumors and are recommended for clinical decision making by ASCO. WX-UK1 is a competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. Methods: Female patients aged >18, with HER2 negative MBC were randomized in a double-blind fashion to receive upamostat (200 mg orally daily for 21 days) plus C (1000 mg/m2 orally twice daily for 14 days) vs. C (same regimen) in 3 week treatment cycles until progressive disease or unacceptable toxicity. 132 from five countries were enrolled. The primary objective was to evaluate the efficacy of the combination of upamostat and C compared to C alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate and safety as well as pharmacokinetics (PK). Efficacy was evaluated by RECIST by independent central read. Results: Median treatment duration was 8 cycles in both arms. In the total study population (intent to treat; ITT) upamostat led to an increase of median PFS from 7.5 months (95% CI: 4.2; 12.8) in the control group to 8.3 months (95% CI: 5.6; 9.6) in the combination therapy. An unexpectedly high rate (50%) of study patients presented within their first two years after initial diagnosis. In patients who had received prior adjuvant chemotherapy, PFS improved from 4.3 months (95% CI: 2.6; 9.7) in the C alone group to 8.3 months (95% CI: 5.6; 10.9) in the upamostat plus C group. The overall response rate was higher in the combination group compared to C alone (20% vs. 12% at Week 24). PK analysis demonstrated no drug-drug interactions between upamostat and C. The combination therapy was safe and well tolerated. Conclusions: This is the first proof of efficacy of an anti-uPA therapy in breast cancer. The heterogeneity of the patients in this study may underestimate the potential treatment effects of upamostat. Additional subset analyses will be presented. Future biomarker-stratified strategies may reveal better efficacy. Clinical trial information: NCT00615940.
Circulating miR-337-3p as a novel biomarker for prostate cancer.
Authors: Valladares Ayerbes Manuel , Medina Villaamil Vanessa , Martinez Breijo Sara , Santamarina Cainzos Isabel , Aparicio Guadalupe , Gonzalez Dacal Jose , Portela Pereira Paula , Vazquez Pazos Dario , Gomez-Veiga Francisco , Antón Aparicio Luis M.
Published: March 2020

5087

Background: Recent studies have demonstrated that the aberrant expression of microRNAs (miRNAs)is related with the development of prostate cancer (PCa). Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information inPCa. The purpose is identifying circulating miRNAs potentially useful for CTC detection in patients with PCa. Methods: In the first study phase we examined blood levels of 92 miRNAs in 49 patients grouped in pools by risk classification: low-risk 42.8%, intermediate-risk 22.5% and high-risk 34.7% and healthy volunteers (N=10) using SYBR-green-based microARN RT-qPCR arrays (Exiqon). Prostate cancer diagnosis was obtained by transrectalultrasound guided biopsy of 10 cores, PSA and digital rectal examination was done previously. In the second study phase using quantitative real-time polymerase chain reaction (qPCR) by TaqMan Human MicroRNAAssays (Life Technologies), we compared the expression levels of miRNAs in blood samples from 34 patients of low-risk, 31 of intermediate-risk, 18 of high-risk localized disease and 22 healthy volunteers paired by age with cases. Receiver-operator characteristic (ROC) curve was used. Results: Blood samples from patients with low, intermediate, high-risk and healthy controls exhibit distinct circulating miRNA signatures. microRNAsdifferential expressed between risk groups (p<0.01) (low, intermediate and high) and control group: 0microARNs upregulated (MU), 12 MU and 68 MU respectively. Highlight the significantlyoverexpression in the intermediate risk group and maintained at the high-risk of microRNAs: 337-3p[247 PicTar predictions (PTP)], 330-3p (307 PTP) and 218 (551 PTP). Preliminary results of the second study phase showed that the median level of miRNA,337-3p was significantly higher in patients with high-risk than that in healthy controls (p=.001). ROC curve analyses indicated that this blood miRNA may beuseful for discriminating patients with high-risk from healthy controls (AUC=.724). Conclusions: miRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. Our preliminary promisingresults suggest miR-337-3p as novel stable blood-based marker for PCa detection.
Effects of abiraterone acetate and enzalutamide on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ileana Ecaterina , Antoun Sami , Albiges Laurence , Massard Christophe , Di Palma Mario , Escudier Bernard J. , Fizazi Karim , Loriot Yohann
Published: March 2020

5088

Background: Abiraterone acetate (AA) and enzalutamide (MDV3100), two androgen receptor-directed compounds, have been shown to improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after Docetaxel.. Since these drugs might be used at an early-stage in the future, and skeletal muscle (SM) and adipose tissue (AT) are known to be prognosis parameters, the aim of this study was to evaluate the body composition changes in patients with mCRPC treated with AA and MDV3100. Methods: Patients included in AFFIRM (n=62 treated with MDV3100 and placebo n=28) and COU-AA-301 (n=24 treated with AA+Prednisone (P)10mg/day and placebo+P n= 13) trials at the Institute Gustave Roussy were included in the analysis. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and SM were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2) with Slice-O-Matic software V4.3 at baseline, 3, 6 and 12 months of treatment. The data from patients treated with AA or MDV3100 were compared to placebo-patients and tissues changes were compared to baseline. We used the validated sarcopenic definitions as SM index less than 52.4 (cm2/m2). Results: For all cohort, median age was 69 years (range: 48-83), median weight was 79 kg (range: 47-150) and median BMI was 25.9 kg/m2(range: 18-46). At inclusion, 74 patients (58%) were overweight or obese (BMI>24.9 kg/m2), and only 2 patients were underweight (BMI<18.5kg/m2). 97 patients (81%) were sarcopenic, and 56 (75%) of overweight or obese patients were sarcopenic. Over 3 months, the patients from the entire cohort lost muscle mass (mean change: 4.5±7.5% (» 0.7 kg of muscle)) (P=0.01) . A non significant loss of SAT -4.6±19.2% and a non significant increase of VAT (+10.7±50.3% ) were observed. A similar pattern was observed at 6 months. There was no significant difference between body composition changes in treated groups and placebo. Conclusions: Sarcopenia is highly prevalent in patients with advanced CRPC. Unexpectedly, no difference in body composition changes was observed between patients treated with MDV3100 or AA and placebo.
Overall survival in hormone-resistant prostate cancer patients with different transition of care within the Veterans Affairs (VA) system.
Authors: Sutton S Scott , Rao Gowtham A , Norris LeAnn B. , Hardin James , Prasad Sandip M. , Bennett Charles L.
Published: March 2020

5091

Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values < 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values <0.001. PSA doubling within 10 months were: 57% tbHRPC, 60% taHRPC, and 54% tnHRPC; p-values < 0.05. Conclusions: Overall survival was improved among prostate cancer patients that transitioned to oncology before becoming HRPC.
A phase Ib study of an anti-HER2 inhibitor, lapatinib, in combination with a c-MET and VEGFR inhibitor, foretinib, in HER2-positive metastatic breast cancer (MBC): Results from NCIC CTG IND.198.
Authors: Chia Stephen K. L. , Ellard Susan , Mates Mihaela , Welch Stephen , Mihalcioiu Catalin Liviu Dragos , Miller Wilson H. , Gelmon Karen A. , Lohrisch Caroline A. , Kumar Vikaash , Taylor Sara Kristina , Hagerman Linda , Eisenhauer Elizabeth A. , Bradbury Penelope Ann
Published: March 2020

518

Background: The mechanisms of resistance to targeted anti-HER 2 therapy are unclear. Proposed pathways include MET, VEGF and AXL. Multi-targeted pathway inhibition may delay or prevent acquired resistance to HER2 inhibition. Foretinib, an oral multi-kinase inhibitor of MET and VEGFR2, as well as PDGFRB, AXL, FLT3, TIE-2, RET and RON kinases, has pre-clinical anti-tumor activity in breast tumor models. This phase 1b study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of this combination of oral tyrosine kinases inhibitors in a cohort of HER-2 positive MBC patients. Methods: Women with HER2 positive (determined locally) MBC, PS 0-2, and no limit on number of prior chemotherapies or lines of anti-HER2 therapies were enrolled. A 3+3 dose escalation design was utilized. 4 dose levels were planned with starting doses of foretinib 30 mg and lapatinib 750 mg PO OD (dose level 1) on a q 4 weekly cycle. Correlative studies from primary archival tissue are planned. Results: 19 patients were enrolled, all of whom were evaluable for toxicity assessment and 16 were evaluable for response. Median age was 60 years (34-86), 95% were PS 0-1, 53% were ER- and 95% had at least one prior anti-HER2 based regimen. A median of 2 cycles (range: 1-20) was delivered across 4 dose levels. At the 4th dose level (foretinib 45 mg/lapatinib 1250 mg) dose limiting toxicities were documented in 4/7 patients. These included grade 3 fatigue (2 cases); grade 3 ALT elevation; grade 3 diarrhea and grade 2 joint effusion. There was only one grade 4 non-hematological toxicity (grade 4 vomiting: dose level 1) across all dose levels. One patient discontinued treatment due to toxicity with grade 3 limb edema and grade 3 proteinuria. PK of both drugs from DL1-3 did not appear to demonstrate a significant interaction. The RP2D was declared to be foretinib 45 mg and lapatinib 1000 mg PO OD. The full efficacy data and correlative studies will be presented at the meeting. Conclusions: The combination of foretinib and lapatinib can safely be delivered together, though at lower doses than either agent alone.
Treatment (tx) patterns and clinical outcomes for patients (pts) with de novo versus recurrent HER2+ metastatic breast cancer (MBC).
Authors: Brufsky Adam , Yardley Denise Aysel , Kaufman Peter Andrew , Ulcickas Yood Marianne , Rugo Hope S. , Mayer Musa , Quah Cheng Seok , Yoo Bongin , Tripathy Debu
Published: March 2020

523

Background: Use of adjuvant trastuzumab (T) in pts with HER2+ early breast cancer is associated with decreased recurrence. As fewer patients relapse, the proportion of pts with de novo metastatic disease in the first-line (1L) setting will increase, which could have implications for the design/interpretation of results from HER2+ MBC trials. To date, little data exist on potential differences in prognosis and outcomes between pts with recurrent vs de novo HER2+ MBC. Methods: registHER is an observational cohort of pts with HER2+ MBC diagnosed ≤6 mo from enrollment and followed until death, disenrollment, or June 2009 (median follow-up: 27 mo). Demographics and 1L tx patterns (using descriptive analyses), as well as clinical outcomes (median PFS and OS estimated by Kaplan-Meier method) were examined for pts with de novo vs recurrent HER2+ MBC. De novo was defined as disease-free interval (DFI) between initial and metastatic diagnosis ≤90 days; recurrent was defined as DFI >90 days. Cox regression analyses were used to generate hazard ratios (HRs). Results: Pts with de novo HER2+ MBC (327 of 1001 enrolled) were more likely to be younger and non-white; have lymph, bone, and/or liver metastases and >4 sites of metastatic disease; less likely to have lung or CNS metastases; and have received 1L regimens of TCH or AC more frequently vs pts with recurrent disease (who received T + vinorelbine more frequently). PFS and OS were longer in the de novo vs recurrent group (Table). Conclusions: Despite presenting with more advanced-stage disease accompanied by higher tumor burdens, pts with de novo HER2+ MBC had more favorable clinical outcomes vs those with recurrent disease. Differences in disease characteristics and tx patterns resulting in more refractory disease (including acquired resistance from adjuvant tx) may account for these observations. Clinical trial information: NCT00105456. [Table: see text]
Long-term (8 years) assessment of trastuzumab-related cardiac events in the HERA trial.
Authors: De Azambuja Evandro , Procter Marion Jennifer , van Veldhuisen Dirk , Agbor-Tarh Dominique , Metzger Filho Otto , Steinseifer Jutta , Untch Michael , Smith Ian E. , Gianni Luca , Baselga Jose , Jackisch Christian , Cameron David A. , Bell Richard , Leyland-Jones Brian , Dowsett Mitchell , Gelber Richard D. , Piccart-Gebhart Martine J. , Suter Thomas
Published: March 2020

525

Background: Trastuzumab-related cardiac dysfunction may occur in patients (pts) treated with adjuvant therapy and it is mostly reversible. We report the long-term outcome of pts with cardiac dysfunction treated with adjuvant trastuzumab (T) in the Herceptin Adjuvant (HERA) trial. Methods: HERA is a three-arm, randomized trial that compared 1 year or 2 years of T with observation (Obs) in women with HER2-positive early breast cancer (EBC). Eligible pts had a left ventricular ejection fraction (LVEF) ≥ 55% at study entry (i.e. after completion of (neo)adjuvant chemotherapy with or without radiotherapy). Cardiac function was closely monitored throughout the trial. This analysis at 8-year median follow-up considers pts randomly assigned to 1 year or 2 years of T therapy or observation. Results: 5102 pts were randomized to HERA. The “as treated” safety population is considered: 2 years T (N=1,673), 1 year T (N=1,682) and Obs (N=1,744). Cardiac events leading to T discontinuation in the 1-year and 2-year arms were observed in 5.2% and 9.4% of pts, respectively. Cardiac death, severe congestive heart failure (CHF) and confirmed significant LVEF drop remained low in all three arms (Table). In the 1 year T arm, 71.4% of pts with severe CHF, and 81.2% of pts with confirmed LVEF drop recovered cardiac function (at least 2 sequential LVEF assessments > 50%). The median time to recovery was 9.7 months and 6.3 months, respectively. In the 2 years T arm, 87.5% of pts with confirmed LVEF drop recovered cardiac function and median time to recovery was 8.3 months. Conclusions: At 8-year median follow-up the incidence of cardiac events during adjuvant T remains low and these events are mostly reversible. These results confirm low cardiac events when T is given as part of the adjuvant therapy for pts with HER2-positive EBC. Clinical trial information: NCT00045032. [Table: see text]
Breast cancer evaluation and targeted investigational therapy (BEAT-IT): A pilot prospective tissue testing to guide clinical trial selection.
Authors: Pusztai Lajos , Mattair Danielle , Ueno Naoto T. , Valero Vicente , Moulder Stacy L. , Murray James L. , Alvarez Ricardo H. , Chavez-Mac Gregor Mariana , Santiago Lumarie , Avritscher Rony , Sahin Aysegul A. , Hortobagyi Gabriel N. , Symmans William Fraser , Meric-Bernstam Funda , Burton Elizabeth M , Gonzalez-Angulo Ana M.
Published: March 2020

532

Background: An increasing number of molecularly targeted drugs are now available in Phase I and II clinical trials. Many of these drugs target specific molecular abnormalities such as mutated, amplified or rearranged genes. Our hypothesis is that cancers that carry a molecular abnormality that corresponds to the mechanism of action of a given investigational drug are more sensitive to that particular drug than other cancers. The objective of this study is to perform molecular analysis of metastatic breast cancer biopsies (bx) using methods already established within CLIA approved laboratories, and to use the results to triage pts to various therapeutic clinical trials or standard of care therapy. Methods: Four core needle biopsies (CNB) and 4 fine needle aspirations (FNA), or 8 FNA are obtained from the most safely accessible metastatic site in a single bx session. Pathological confirmation of successful aspiration is performed. Two core bx (or 4 FNA passes) are formaldehyde fixed and paraffin embedded for Immunohistochemistry (IHC), FISH and mutation analysis (CMS11 or CMS46) and 4 FNA are placed in RNA-later and snap-frozen for transcriptional profiles and storage. Samples are transferred to the Molecular Diagnostic, IHC, and Cytogenetics Laboratories. All reports are included in the electronic medical record. Results: FromFeb 2012 to Jan 2013, 142 pts referred, 128 pts registered, 101 bx completed and 78 (77%) bx with available results. Bx sites included: liver (37), lymph node (26), soft tissue (16), bone (13), lung (5), other (4). Successful results were obtained for IHC: PTEN (73%), AR (78%), MET (73%), FISH: EML4-ALK (78%) and MET (74%), and mutation analysis (76%). To date, there have been no reported hospitalizations, ER visits, bleeding, pain, infection or organ dysfunction at the bx sites. 16 pts have been treated on trials with investigational agents hypothesized to result in response based upon the molecular profile of the tumor. Conclusions: Prospective tissue collection to determine the molecular targets and to evaluate pts for clinical trial selection is feasible and safe.