bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Danila Daniel Costin , Szmulewitz Russell Zelig , Higano Celestia S. , Gilbert Houston , Kahn Robert S. , Wood Katie , Agarwal Priya , Lin Kedan , Kabbarah Omar , Fine Bernard M. , Maslyar Daniel J. , Vaishampayan Ulka N.
Published: March 2020

5020

Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (<5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ≥ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.
Automated quantum dots ISH assay for detection of ERG rearrangement and PTEN deletion in prostate cancer.
Authors: Tang Lei , Zhang Wenjun , Hubbard Antony , Brunhoeber Patrick S , Wang Yixin
Published: March 2020

5045

Background: ERG rearrangement and PTEN deletion are the two most common genomic events in prostate cancer. Overexpression of the ERG protein caused by rearrangement of the ERG gene has been frequently associated with more aggressive prostate cancers and a poor prognosis. PTEN genomic deletion and absence of PTEN expression are associated with unfavorable clinical outcome. To detect ERG rearrangement and PTEN deletion simultaneously, we developed a four-color multiplex ISH assay using non-organic quantum dots (QD). The photo-stability and narrow emission spectra of QDs makes them desirable for ultrasensitive and multiplexing ISH applications. The automated QD ISH assay allows adequate delivery of QDs to nuclear targets and reproducible detection of ERG and PTEN gene targets. Methods: DNA probes specific for ERG 5’, ERG 3’, PTEN and CEN 10 were labeled with different haptens, digoxigenin (DIG), dinitrophenyl (DNP), thiazole sulfonamide (TS), or nitropyrazole (NP). QDs with 565, 655, 605 and 525nm wavelengths were conjugated to the anti- DIG, DNP, TS or NP antibodies, respectively. The multiplex QD ISH assay was fully automated on the VENTANA BenchMark ULTRA. FFPE prostate tissue slides were hybridized with the labeled probes. The probes were then detected by the QD-conjugated antibodies and visualized under fluorescent microscope. Results: We performed the multiplex QD ISH assay on 386 slides with tissue sections from 10 prostate specimens on 13 BenchMark ULTRA instruments. The 10 cases consisted of either benign prostate tissues or prostate cancer, positive or negative for ERG rearrangement and/or PTEN deletion. 350 (91%) of the slides were successfully stained for all 4 molecular targets. The expected ERG and PTEN status were detected with high reproducibility. Conclusions: We developed an automated QD based multiplex ISH assay to simultaneously detect ERG rearrangement and PTEN deletion in prostate cancer. The assay is highly sensitive and reproducible. It enables investigation of potential clinical use of ERG and PTEN as predictive or prognostic markers. In addition, the same technology is expected to enable multiplex in situ detection of other molecular biomarkers using standard clinical specimens.
Profile study: Genetic prostate cancer risk stratification for targeted screening.
Authors: Castro Elena , Bancroft Elizabeth , Taylor Natalie , Dadaev Tokhir , Page Elizabeth , Keating Diana , Borley Nigel , DeSouza Nandita , Saunders Ed , Lee Andrew , Neal David , Antoniou Antonis C. , Kote-Jarai Zsofia , Eeles Ros A.
Published: March 2020

5054

Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA<3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.
A pilot phase II study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA.
Authors: Lin Jianqing , Hoffman-Censits Jean H. , Duffy Danielle , Chervoneva Inna , Kilpatrick Deborah , Kennedy Brooke , Trabulsi Edouard John , Lallas Costas D. , Gomella Leonard G. , Force Thomas , Kelly William Kevin
Published: March 2020

5061

Background: Hypoxia-inducible factor 1α (HIF-1α) is a novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides were found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in mouse model. Epidemiologic data showed that use of digoxin in men was associated with a significant lower risk of development of PCa. We hypothesized that therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: Open label, non-placebo pilot study. Non-metastatic, biochemically relapsed PCa patients (pts) with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to therapeutic level (0.8 – 2 mg/dl) and pts had routine follow-up that include cardiac monitoring with EKG. The primary endpoint was to evaluate the proportion of patients at 6 month post-treatment that had a PSADT > 200% from the baseline. Results: Fifteen pts were enrolled into the study with 13 pts finishing the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline. At 6 months, 7 of 15 (47%) pts had PSADT > 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Mean duration of digoxin treatment was 34.5 weeks. Digoxin was well tolerated with possible relation of one grade 3 back pain and one grade 2 hyperglycemia. No pts came off study due to cardiac reasons. Pre-and post-treatment PSA kinetics, vascular endothelial growth factors and other cytokines levels are being determined. Conclusions: Digoxin was well tolerated and showed a prolongation in the PSDAT in 47% of the patients. Digoxin may have biologic activity in men with androgen-dependent PCa but further controlled studies are required to confirm the results. Clinical trial information: NCT01162135.
Use of [-2]proPSA and prostate health index (phi) to improve the diagnostic accuracy of prostate cancer compared to t-PSA and %f-PSA in young men (≤ 65 years old).
Authors: Boegemann Martin , Vincendeau Sebastien , Stephan Carsten , Houlgatte Alain , Krabbe Laura-Maria , Semjonow Axel , Blanchet Jean-Sebastien
Published: March 2020

5074

Background: Although prostate-specific antigen (tPSA) screening reduced prostate cancer (PCa) mortality recent recommendations do not endorse PSA-screening due to overdiagnosis and overtreatment and the resulting harm afflicted to patients. Screening studies showed the maximum benefit in young men < 65 years of age. tPSA and percent free PSA (%fPSA) lack specifity in the diagnosis of PCa. [-2]proPSA and the prostate health index (phi) improved this diagnostic specifity. Markers to diagnose clinicaly relevant cancers in young men are needed. Methods: The clinical performance of [-2]proPSA and phi was evaluated in a multicenter study. A total of 1362 patients scheduled for initial or repeated prostate biopsy (668 with, 694 without PCa, each ≥ 10 core biopsies) were recruited in 4 different sites based on PSA level 1.6 – 8.0 ng/mL WHO-calibrated (2-10 ng/mL classically calibrated). Serum samples taken prior to digital rectal examination (DRE) were measured for the concentration of tPSA, fPSA and [-2]proPSA with Beckman Coulter immunoassays on Access 2 or DxI800 instruments. Phi was calculated as [-2]proPSA/fPSA*√tPSA. Results: In univariate analysis [-2]proPSA/fPSA (%[-2]proPSA) and phi were the best predictors of PCa detection in patients at initial biopsy (AUC: 0,72 and 0,73) and repeated biopsy (AUC: 0,74 and 0,74). Analysis of the data for men ≤ 65 years of age (n=593) showed that %[-2]proPSA and phi significantly improved PCa dectection (AUC: 0,72 and 0,73) as compared with tPSA (AUC: 0,54) or %fPSA (AUC: 0,62). In the detection of significant PCa (based on PRIAS criteria) %[-2]proPSA and phi demonstrated the best performance in the whole cohort and in young men (≤ 65) years as well (AUC 0,68 and 0,73). Conclusions: This multicenter study showed that [-2]proPSA and phi have a superior clinical performance in detecting PCa in the PSA range of 2-10 ng/mL compared with tPSA and %fPSA at initial and repeated biopsies. This superiority is maintained for the detection of PCa in young men (≤ 65 years of age).
Safety, efficacy, and health-related quality of life (HRQoL) of the investigational single agent orteronel (ortl) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Hussain Maha , Corn Paul Gettys , Michaelson M Dror , Hammers Hans J. , Alumkal Joshi J. , Ryan Charles J. , Bruce Justine Yang , Moran Susan , MacLean David , Lee Shih-Yuan , Lin H. Mark , Zhu Yanyan , Shi Hongliang , Mortimer Peter , George Daniel J.
Published: March 2020

5076

Background: Ortl is a selective, non-steroidal, oral 17,20-lyase inhibitor. Due to its lower inhibition of 17α-hydroxylase vs 17,20-lyase, ortl may allow steroid-free dosing. Ortl 300 mg BID was studied in nmCRPC patients (pts). Methods: Pts with nmCRPC, PSA ≥2 ng/mL (PSA ≥8 ng/mL if doubling time >8 mo), and testosterone (T) <50 ng/dL received ortl 300 mg BID until PSA progression, development of metastases (mets), or unacceptable toxicity. Primary endpoint: the percentage of pts with PSA ≤0.2 ng/mL at 3 mo. Secondary endpoints included safety, PSA kinetics, time to mets, and PFS (PSA progression, mets, or death), endocrine and bone markers, bone mineral density (BMD), HRQoL, cardiac and lipid assessments. Results: 38 pts enrolled: median PSA 11.7 ng/mL (range 2.6–67.8), T 8.5 ng/dL (1.4–17.3), and ACTH 20 ng/L (n=32; 0–47). Median therapy duration was 12.4 mo (0.7–27.8); 55% of pts were treated >12 mo. 6 had dose reduction, 12 discontinued due to adverse events (AEs), including 2 for possible adrenal insufficiency. Gr 3 hypertension occurred in 7 pts (18%); various ≥Gr 3 AEs occurred in another 14 pts; 10 pts (26%) had serious AEs. At 3 mo, median T declined 89% to 0.78 ng/dL; median ACTH increased 171%; median cortisol declined 21%, but remained within normal range. 97% of pts had PSA declines; median PSA declined 83%. 18% had PSA ≤0.2ng/mL at 3 mo; 32% achieved PSA ≤0.2ng/mL as best response. Median time to PSA progression was 13.8 mo. Median PFS was 13.8 mo. Kaplan-Meier estimates of 1 and 2 y mets-free rates were 94% and 69%, respectively; 8 pts developed mets on study. The patient-reported Aging Male Symptoms Scale showed no decrease in overall scores, psychological, somatic, or sexual domains in 37, 34, 25, and 19 pts assessed at visits 2, 4, 7, and 13, respectively. Serum lipids, cardiac assessments, HbA1C, or bone-specific enzymes (N-telopeptide, or BMD) were not adversely affected. Conclusions: In pts with nmCRPC, long-term steroid-free ortl was feasible, with clinical activity as reflected by sustained marked declines in PSA and T, and had manageable toxicities, with no adverse effects on HRQoL, cardiac, bone or lipid profiles. Clinical trial information: NCT01046916.
Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate resistant prostate cancer (CRPC).
Authors: Aggarwal Rahul Raj , Weinberg Vivian K. , Sosa Eduardo V. , Lin Amy M. , Harzstark Andrea Lynne , Small Eric Jay , Fong Lawrence , Hsieh Andrew Caleb , Formaker Carl , Koepfgen Kathryn M. , Hang Evelyn , Friedlander Terence W. , Ryan Charles J.
Published: March 2020

5077

Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase II study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of > 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]
Ejaculation frequency and prostate cancer: A large, prospective study with 16 years of follow-up.
Authors: Rider Jennifer R , Wilson Kathryn M , Kantoff Philip W. , Giovannucci Edward L. , Mucci Lorelei A.
Published: March 2020

5078

Background: A prospective study in the Health Professionals Follow-up Study (HPFS) cohort published in 2001 found significantly lower risks of prostate cancer (PCa) among men with more frequent ejaculation. Because associations were stronger among men at older ages, which could be indicative of reverse causation (i.e., men ejaculating less because of symptoms associated with PCa) and few advanced cases were included, we conducted an updated study with an additional 8 years of follow up. Methods: We included 31,929 men aged 46-81 years from the HPFS who answered ejaculation frequency questions on the 1992 questionnaire. We assessed average frequency per month at three time points: age 20-29, age 40-49, and in 1991 (the year prior to the questionnaire). These data were also combined to estimate average lifetime frequency. Using follow up through January 31, 2008, we used Cox proportional hazards models to estimate relative risks (RR) and 95% confidence intervals (95% CI) for total PCa risk, as well as risk of advanced, lethal, and high-grade (Gleason 8-10) disease. As sensitivity analyses, we also examined associations within a subgroup of highly screened men and a subgroup of men without erectile dysfunction at baseline. Results: During 16 years of follow up, 3403 men were diagnosed with PCa; 455 were advanced, 360 were high grade, and 304 were lethal. Three percent of men reported a lifetime average frequency of >21 times per month while 34% reported 4-7 times per month. Compared to a frequency of 4-7 times per month, multivariate RRs for total PCa for men with >21 ejaculations per month were 0.81 (95% CI: 0.71-0.91) for ages 20-29; 0.76 (95% CI: 0.66-0.88) for ages 40-49; 0.68 (95% CI: 0.53-0.86) in 1991; and 0.57 (95% CI: 0.43-0.75) for lifetime average frequency. RRs for advanced PCa were of similar magnitudes at ages 20-29 years and 40-49 years but not statistically significant. Results were similar when we included only highly screened men or men without a history of erectile dysfunction. Conclusions: With extended follow up, ejaculation frequency continues to be strongly inversely associated with risk of total PCa. These findings are unlikely to be attributable to underlying disease or screening frequency.
Correlation between baseline variables and survival in the radium-223 dichloride (Ra-223) phase III ALSYMPCA trial with attention to total ALP changes.
Authors: Sartor A. Oliver , Amariglio Roy , Wilhelm Scott , Garcia-Vargas Jose E. , O'Bryan-Tear C. Gillies , Shan Minghua , Fang Fang , Parker Chris
Published: March 2020

5080

Background: In patients (pts) with castration-resistant prostate cancer and bone metastases (mCRPC), total ALP (tALP) has been shown to be a prognostic marker for overall survival (OS) (Cook 2006). Here the prognostic value of tALP and other baseline clinical variables in Ra-223 pts is presented, along with the initial results of an exploratory analysis of changes in tALP seen with Ra-223. Methods: Study population included 921 pts (intent-to-treat population) from the ALSYMPCA trial. The Cox proportional hazards model was used to evaluate the prognostic potential of tALP and other baseline variables (albumin, Hb, LDH, ECOG performance status, PSA, and age). Log transformation was done for baseline variables (tALP, PSA, and LDH) with heavily skewed distributions. Baseline variables were assessed for interaction with treatment. To determine changes in tALP from baseline at 12 wk, 708 pts who had tALP measurements at both baseline and 12 wk were included. Results: The baseline variables in the Table were significantly associated with OS. Hb was not a significant factor when adjusting for all other covariates and was therefore removed from the final Cox regression model. No significant treatment-by-covariate interactions were detected. After controlling for other variables, higher baseline tALP was significantly associated with an increased risk of death (p < 0.0001). At 12 wk, a decline in tALP relative to baseline was seen in 87% (433/497) of Ra-223 pts, compared to 23% (49/211) of placebo pts. The mean percentage change from baseline in tALP at 12 wk was a 32% decline for Ra-223 pts, in contrast to a 37% increase for placebo pts (p< 0.001). Conclusions: In mCRPC pts, higher baseline levels of tALP were associated with an increased risk of death. With the majority of Ra-223 pts experiencing a decline in tALP at 12 wk, and the marked mean percentage tALP decline in these pts, further analysis to determine a correlation between tALP dynamics and survival is warranted. Clinical trial information: NCT00699751. [Table: see text]
Association of germ-line genetic variation with failure of androgen ablation (AA) in hormone-sensitive advanced prostate cancer.
Authors: Kohli Manish , McDonnell Shannon , Bevan Graham H. , Riska Shaun M. , Costello Brian Addis , Longenbach Sherri , Dronca Roxana Stefania , Moynihan Timothy Jerome , Pitot Henry Clement , Quevedo Fernando , Tan Winston , Cerhan James Robert
Published: March 2020

5082

Background: We evaluated the association of germ-line variation in 10 candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with failure of AA in advanced prostate cancer patients. Methods: Patients (N=619) were enrolled for genotyping at the time of AA failure. Candidate genes were selected from the literature and previous pilot studies in smaller cohorts which had identified variation in TRMT11 and HSD17B12 to be associated with AA failure. Genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of >5% and r2≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was time to failure on AA, defined as time from initiating continuous AA to two serial PSA increases over the nadir or clinical or imaging based progression, whichever came first. Principal component analysis was used for gene-levels tests. Association with the primary endpoint was assessed using proportional hazards regression models at the gene-level and at the SNP level. For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression, adjusted for Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 519 subjects. The median age of the cohort was 71 years (range 43, 92). The GS distribution was 51% subjects with GS≥8; 33% with GS=7 and 17% with GS<7. Median time to AA failure for the cohort was 2.3 years (IQ range: 1.0-4.5). In gene level analyses adjusting for GS, TRMT11 (p=0.004), HSD17B12 (p=0.016), and JAK2 (p=0.044) genes were associated with time to AA failure. Four of the 18 genotyped SNPs in JAK2 were associated with AA failure after adjustment for GS (Table). Conclusions: Variation in the JAK2 gene is significantly associated with time to AA failure. Validation is needed to develop these as predictive biomarkers for AA in advanced prostate cancer. [Table: see text]
The role of advanced genetic testing in the management of prostate cancer post radical prostatectomy.
Authors: Schaeffer Edward M. , Vergara Ismael A. , Crisan Anamaria , Erho Nicholas , Ghadessi Mercedeh , Feng Felix Yi-Chung , Davicioni Elai , Ross Ashley E.
Published: March 2020

5089

Background: The genomic classifier (Decipher, GC) is a prospectively validated assay that predicts clinical metastasis post radical prostatectomy (RP) more accurately than standard clinicopathologic factors. While over 70% of high risk patients tested in a previous validation had low GC scores and good prognosis, patients with high GC scores had a cumulative incidence of metastasis over 25% over the study duration. Among men diagnosed with localized prostate cancer, these most at risk patients may derive the greatest benefit from novel therapies. We thus examined differential expression (DE) of druggable genes that may be targeted in this group. Methods: High-density microarray expression profiles of primary FFPE tumor specimens from 764 men treated with RP at the Mayo Clinic (1987-2006) were evaluated. A subset of 323 patients was flagged as high risk of clinical metastasis (mets) by virtue of having GC score ≥ 0.4. Enrichment and identification of DE genes as druggable targets were pursued using DAVID and DrugBank. Results: Median follow-up of patients was 15.1 years. Among the 323 patients with high GC scores, 62% had mets during follow-up.We identified 2,262 genes DE between mets and non-mets, 230 of which are associated with 331 approved pharmaceuticals and 547 experimental agents. These agents included multiple established anti-neoplastic therapies not currently used to treat prostate cancer such as bortezomib, capecitabine, dasatinib, etoposide, gemcitabine, imatinib, irinotecan, pemetrexed and vinblastine. The two most enriched pathways, spliceosome and ubiquitin-mediated proteolysis, have been proposed previously as therapeutic targets in cancer. Conclusions: Advanced genomic testing that includes validated molecular risk scores as well as transcriptome profiling from a single assay may better enable application of directed, multimodal therapy for individual patients with high risk prostate cancer.
Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).
Authors: Lin Nancy U. , Gelman Rebecca Sue , Younger W. Jerry , Sohl Jessica , Freedman Rachel A. , Sorensen A. Gregory , Bullitt Elizabeth , Harris Gordon J , Morganstern Daniel , Schneider Bryan P. , Krop Ian E. , Winer Eric P.
Published: March 2020

513

Background: The anti-tumor and anti-edema effects of BEV provide a rationale for testing in BCBM. Carboplatin (C) is associated with CNS responses across multiple tumor types. We evaluated BEV + C in pts with BCBM. Methods: Pts with progressive, measurable BCBM (>/= 1 cm in longest dimension) were eligible. Cycle 1: BEV 15 mg/kg on Day 1, followed on Day 8 by carboplatin AUC=5 (plus trastuzumab if HER2+). In subsequent cycles, pts received BEV + C on Day 1 (plus trastuzumab if HER2+) of a 3 week (wk) cycle. Standard brain MRI was obtained at baseline (BL) and every 2 cycles. Non-CNS scans (CT or MRI) were performed after 2 cycles, 4 cycles, then every 4 cycles. Correlative brain imaging was obtained at BL, 12-96 hours after the first dose of BEV, and after 2 cycles. Circulating tumor cells and blood for VEGF polymorphisms were also collected. The primary endpoint was composite CNS objective response rate (CNS ORR). CNS partial response required all of the following: >/= 50% reduction in volumetric sum of target CNS lesions compared to BL, no progression of non-target lesions, no new lesions, stable/decreasing steroid dose, no progressive neurologic signs or symptoms, and no progression of non-CNS disease by RECIST 1.0. The study used a 2-stage design to distinguish between ORR 5% vs 20% (responses in >/= 1/12 pts to enter 2ndstage; responses in >/= 4/37 pts needed to be promising). Results: 38 pts were enrolled between 11/3/09-8/24/12 (30 HER2+; 8 HER2-negative). Most (76%) pts had received >/=2 lines of metastatic chemotherapy. 97% of pts with HER2+ disease received prior trastuzumab; 73% had prior lapatinib. All but 5 pts progressed after WBRT and/or SRS. As of 1/15/13, 3 pts remain on protocol therapy; 22 patients have died. The composite CNS ORR was 63% (95% CI 46%-78%). CNS ORR by RECIST was 45%. CNS responses were observed in both HER2+ and HER2-negative pts. Of 34 pts with >/= 24 wks potential follow-up time, median number of cycles was 8 (range 1-19). One grade 2 CNS hemorrhage event was reported; there were no cases of grade 3/4 CNS hemorrhage. Conclusions: BEV + carboplatin is associated with a high rate of durable CNS response in pts with BCBM. Updated results, including progression-free and overall survival will be presented. Clinical trial information: NCT01004172.
TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) central nervous system (CNS) metastases (mets).
Authors: Anders Carey K. , Deal Allison Mary , Abramson Vandana Gupta , Liu Minetta C. , Storniolo Anna Maria , Carpenter John T. , Puhalla Shannon , Nanda Rita , Melhem-Bertrandt Amal , Lin Nancy U. , Marcom Paul K. , Van Poznak Catherine H. , Stearns Vered , Melisko Michelle E. , Smith J. Keith , Karginova Olga , Winer Eric P. , Perou Charles M. , Wolff Antonio C. , Carey Lisa A. ,   Translational Breast Cancer Research Consortium
Published: March 2020

515

Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (> 5mm) lesion. Pts received irinotecan 125mg/m2 IV days (d) 1, 8 and iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mutation (4 BRCA1, 1 BRCA2). 88% received prior (neo)adjuvant and 68% prior metastatic chemotherapy (median 2 [1–14] lines). While 15% were CNS radiation (RT) naïve, 32% had received whole brain RT, 21% stereotactic RT, and 32% both. The most common grade (gr) 3/4 adverse events were neutropenia (14%), fatigue (5%), leukopenia (5%), hypokalemia (5%). Diarrhea was common (54%), but gr 3/4 was rare (3%). Median TTP (CNS and non-CNS) was 2.1 months (mos) (95% CI 1.7–4.3) and OS was 7.6 mos (95% CI 5.1-10.2). First progression site was CNS in 39%, non-CNS in 29% or both in 32%. CNS best RR was (12%; 0 CRs, 4 PRs); CNS clinical benefit rate (CBR, CR + PR + SD ≥ 6 mos) was 30%. Non-CNS RR was 5% (0 CRs, 1 PR) and CBR was 11%. Conclusions: Iniparib and irinotecan was well-tolerated among pts with TNBC CNS mets. While TTP was shorter than expected and contribution of iniparib to irinotecan remains uncertain, 30% of pts demonstrated CNS clinical benefit raising the question of whether predictive biomarkers could be identified. QOL, volumetric analysis of CNS lesions and translational studies evaluating molecular subtype, germline BRCA1/2, and DNA repair gene expression/methylation are ongoing. Clinical trial information: NCT01173497.
Is the proportion of patients with synchronous stage IV breast cancer surviving > 2 years increasing over time?
Authors: Dawood Shaheenah S. , Haaland Benjamin , Albarracin Constance T. , Gonzalez-Angulo Ana M. , Gupta Sudeep , Cortes Javier , Yap Yoon Sim , Dent Rebecca
Published: March 2020

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Background: Studies have shown a moderate increase in survival over time among pts with stageIV breast cancer. Median survival is approximately 2 yrs. The aim of this study was to evaluate trends over time of pts with synchronous stage IV disease who survive >2 yrs. Methods: Using the SEER registry we identified female pts with synchronous stage IV breast cancer diagnosed between 1990-2007. Pts were divided into 3 groups according to year of diagnosis(1990-1995, 1996-2000, 2001-2007). Probability of surviving more than >2 yrs was computed within each group. A multivariable logistic regression model was then fitted to determine the association between year of diagnosis and the probability of surviving >2 yrs after adjusting for other prognostic factors. Results: 22,492 pts were identified of whom 9,388 (41.7%) had a survival of >2 yrs. The probability of surviving >2 yrs was 36.2%, 40.1%, and 44.2% among pts diagnosed in periods 1990-1995, 1996-2000, and 2001-2007 respectively (p-value < 0.0001). The probability of surviving >2 yrs was 55.3% and 29.3% among pts with ER+ and ER- disease respectively (p-value <0.0001) and was 32.9% and 43.5% among pts of black and white race respectively (p-value <0.0001). In the multivariable model the probability of surviving >2 yrs increased with increasing year of diagnosis (OR 1.04, 95% CI 1.03-1.05, p <0.0001). Other factors significantly associated with an increased probability of surviving >2 yrs included radiation therapy, lower grade, younger age, hormone receptor (HR) positive disease and non-inflammatory disease. Interaction term between race and year of diagnosis was marginally significant, such that black pts had a more slowly increasing probability of surviving >2 yrs compared to whites (OR 0.97, 95% CI 0.96-1.00, p = 0.037). Interaction term between HR status and year of diagnosis was not significant. Conclusions: Our results indicate that among pts with synchronous stage IV breast cancer the probability of surviving >2 yrs has increased over time reflecting the introduction and FDA approval of multiple efficacious chemotherapeutic and endocrine therapeutic options. Of concern, the probability of surviving >2 yrs has increased more slowly among pts of black race.
Preoperative letrozole plus lapatinib/placebo for HR+/HER2 negative operable breast cancer: Biomarker analyses of the randomized phase II LET-LOB study.
Authors: Guarneri Valentina , Frassoldati Antonio , Generali Daniele Giulio , Bottini Alberto , Cagossi Katia , Bisagni Giancarlo , Boni Corrado , Cavanna Luigi , Piacentini Federico , Bettelli Stefania Raffaella , Ficarra Guido , Maiorana Antonino , Marini Luca , Conte Pier Franco
Published: March 2020

530

Background: This is a randomized, double-blind, placebo controlled study aimed to evaluate the clinical and biological effects of letrozole + lapatinib or placebo as neoadjuvant therapy in previously untreated hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal patients with stage II-IIIA breast cancer were randomly assigned to 6 months letrozole-lapatinib (Arm A, n=43) or letrozole-placebo (Arm B, n= 49). Clinical response was evaluated according to RECIST. The following biomarkers were centrally evaluated by IHC on diagnostic core biopsy and on surgical specimens: HER2, Ki-67, EGFR, pAKT, PTEN. PIK3CA mutations were evaluated by pyrosequencing. Results: 81 patients were evaluable by USG, 8 were assessed with mammography and/or palpation. Three patients who discontinued therapy and withdrew consent were counted as non-responders according to the ITT analysis. No differences in terms of objective response rate (partial+complete response) were observed between the two arms (70% vs 63%). The percentage of patients achieving disease progression, disease stabilization, partial response and complete response were 2%, 23%, 58%, 12% respectively in the letrozole-lapatinib arm, and 6%, 29%, 61%, 2% respectively in the letrozole-placebo arm. No patients achieved pCR. All the patients were centrally confirmed as having HER2 negative disease. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. A trend for a greater Ki67 suppression was observed in responding patients (mean Ki67 suppression -8.8 in responders vs -3.6 in non responders, p= 0.06). A mutation in PIK3CA exon 9 or 20 was observed in 37% of the patients. Overall, no differences in response were observed according to PIK3CA mutations, however, in the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the PIK3CA mutation subgroup (ORR 93% vs 63% in PIK3CA WT, Pearson’s chi2 p=0.040). Conclusions: This is the first trial showing a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in Hormone Receptor +/HER2- disease. Clinical trial information: NCT00422903.
Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.
Authors: Bardia Aditya , Isakoff Steven J. , Juric Dejan , Borger Darrell R. , Dias-Santagata Dora , Iafrate Anthony John , Flaherty Keith , Moy Beverly , Ellisen Leif William
Published: March 2020

533

Background: Major barriers to enrollment in therapeutic clinical trials (<5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.
Frequent LOH of CYP2D6 in ER+ breast cancer determined by next-generation sequencing (NGS).
Authors: Ratain Mark J. , Sun James , Nakamura Yusuke , Cox Nancy J , Sahmoud Tarek , Stephens Phil , Chen David , Miller Vincent A. , Ross Jeffrey S. , Yelensky Roman
Published: March 2020

534

Background: The role of CYP2D6 genetic variation in predicting response to tamoxifen in ER+ breast cancer is a subject of ongoing debate. There has been great variability in approaches to both genotyping and phenotyping, and in particular many investigators have extracted DNA from breast cancer samples rather than peripheral blood. We hypothesized that CYP2D6 gene copy number alterations are common in ER+ breast cancer, affecting genotype results, and used NGS to characterize CYP2D6 in patients with ER+ disease. Methods: CYP2D6 sequencing was performed as part of a comprehensive NGS profile of cancer-related genes for 261 predominantly relapsed and metastatic ER+ breast cancer FFPE specimens. Sequence data were resolved into genotypes according to the * allele nomenclature. Tumor LOH was determined at CYP2D6, and its error impact on genotyping methods was estimated. To assess biological significance, the prevalence of CYP2D6 alleles and LOH in ER+ disease was compared against a control set of 99 ER- tumors. Results: CYP2D6 allele frequencies in our full cohort (ER+, 261; ER-, 99) were consistent with prior studies; 64.4%, 16.8%, 9.0% vs. 63.1%, 17.2%, 7.0% for *1/*2, *4, and *41 respectively, and 1%-2% for the rarer alleles *9, *10, and *5. The rate of CYP2D6 LOH was higher in ER+ disease (41% vs. 26%, p<0.01), with all excess arising from copy-loss (as opposed to copy-neutral) changes (22% vs. 7%, p<0.002). The estimated impact of LOH on germline genotype assessment from tumor was considerable; an assay sensitive at >20% minor allele frequency (e.g., Sanger sequencing) can misclassify >10% of heterozygotes, leading to significant Hardy-Weinberg disequilibrium (e.g., p=8.3x10-8 for *4). Interestingly, an enrichment of reduced or non-functional CYP2D6 alleles in ER+ samples was observed (61% vs. 47%, p<0.03). Conclusions: Our results demonstrate the distorting effect of extensive LOH on genotype assessment of CYP2D6 in breast cancer. Therefore, tumor DNA should not be routinely used for determination of germline 2D6 genotype, although it appears possible to use NGS. The apparent association between reduced function CYP2D6 alleles and ER+ breast cancer in our dataset requires further investigation.
Final results of a phase II trial of trabectedin (T) in patients with hormone receptor-positive, HER2-negative advanced breast cancer, according to xeroderma pigmentosum gene (XPG) expression.
Authors: Awada Ahmad , Cortes Javier , Martin Miguel , Aftimos Philippe , Oliveira Mafalda , Espie Marc , Lardelli Pilar , Extremera Sonia , Kahatt Carmen Maria , Delaloge Suzette ,   PharmaMar
Published: March 2020

547

Background: Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (BC) is currently associated with 3-4 years survival and, after ≥2 relapses, therapeutic approaches are reduced. XPG expression is frequently modified in BC. T forms cytotoxic complexes with XPG inducing apoptosis, thus, the inhibitory effects of T may depend on XPG presence. In fact, a better response to T in BC pts with XPG RNA overexpression has been observed. Methods: Pts withHR positive, HER2 negative advanced BC, pretreated with anthracyclines and/or taxanes, who had progressed after 2-5 chemotherapy lines, were stratified according to their XPG expression from paraffin embedded tumor samples, to stratum A (XPG high [>3]) or to stratum B (XPG low [≤3]) (threshold was selected from median XPG expression values observed in a previous trial) and treated with T (1.3 mg/m2 in 3-hour iv infusion every 3 weeks). Primary endpoint: to evaluate the efficacy of T as progression free survival rate at 4 months (PFS4) according to XPG expression. Secondary endpoints: Comparison of PFS, overall response rate, duration of response, overall survival and safety in XPG high and XPG low pts. Statistical methods: A 2-stage design was chosen: at a 1st stage, 20 pts were enrolled in each stratum. A futility analysis (O’Brien Fleming boundary) based on the primary endpoint was done once 40 evaluable pts were recruited. If ≥ 7 out of 20 pts achieved PFS4, recruitment would continue to a maximum of 50 pts per stratum. Results: 44 pts (21 XPG high and 23 XPG low) were enrolled from three countries and five centers. Efficacy is shown in the Table. Most frequent AEs were nausea (54%) and fatigue (70%). ALT increase G4 occurred in 7% of pts and neutropenia G4 in 28%. Conclusions: Trabectedin showed modest activity in advanced HR-positive, HER2-negative BC previously treated with anthracyclines and taxanes, with an acceptable safety profile. XPG does not seem to be a predictor of outcome to T treatment in this patient population. Clinical trial information: 2010-022968-13. [Table: see text]
Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial.
Authors: Kehoe Sean , Hook Jane , Nankivell Matthew , Jayson Gordon C. , Kitchener Henry Charles , Lopes Tito , Luesley David , Perren Timothy , Bannoo Selina , Mascarenhas Monica , Dobbs Stephen , Essapen Sharadah , Twigg Jeremy , Herod Jonathan , McCluggage W. Glenn , Parmar Mahesh , Swart Ann Marie
Published: March 2020

5500

Background: First line treatment of advanced ovarian cancer (OC) is accepted to be primary surgery (PS) followed by adjuvant platinum-based chemotherapy (P-CT). However, the EORTC55971 trial suggested neoadjuvant chemotherapy (NACT) is an alternative, showing increased optimal debulking rates and reduced surgical complications without detriment to survival. CHORUS (CRUK 07/009) is the 2nd phase III randomized controlled trial to investigate timing of initial surgery in OC. Methods: Patients (pts) with clinical FIGO stage III-IV OC (pelvic mass, extrapelvic metastases and CA125/CEA ratio >25) were randomized to standard treatment (PS followed by 6 cycles P-CT) or NACT (3 cycles P-CT either side of surgery). CHORUS was designed to demonstrate non-inferiority of NACT, excluding a 6% absolute detriment in 3yr survival from 50% expected with PS (1-sided alpha 10%). Primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), toxicity and quality of life. Results: 550 women (276 PS, 274 NACT) were randomized from 74 centres (72 UK, 2 NZ) between Mar 2004 and Aug 2010. Baseline characteristics were well balanced: median age 65yrs, median tumor size 80mm, 25% FIGO stage IV, 19% WHO PS 2. Median follow-up was 3yrs, 410 pts have died. Treatment data are summarized in the Table. 3yr survival in the control arm was 32%. Intention to treat analysis showed a median OS of 22.8 months for PS vs 24.5 months for NACT (hazard ratio (HR) 0.87 in favor of NACT, 80% CI 0.76 – 0.98) and median PFS of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). OS results represent a 5% absolute benefit in 3yr survival for NACT to 37% and the upper 80% CI allows us to exclude a survival benefit for PS. Conclusions: NACT was associated with increased optimal debulking, less early mortality and similar survival in this poor prognosis group. CHORUS results are consistent with EORTC55971 and strengthen evidence that NACT is a viable alternative to PS. Clinical trial information: ISRCTN74802813. [Table: see text]