bluuebunny/crossref_metadata_2025 huggingface dataset:
Intermediate prognosis in metastatic germ cell tumors (IPGCT): Outcome and prognostic factors.
Authors: Seidel Christoph Alexander , Daugaard Gedske , Tryakin Alexey , Necchi Andrea , Hentrich Marcus , Cohn-Cedermark Gabriella Elisabeth , Stahl Olof , Goncalves Margarida Brito , Gerl Arthur , Oechsle Karin , Bokemeyer Carsten
Published: September 2018

4560

Background: The IGCCCG classification published in 1997 is based on data from the 1970-80s. Approximately 25% of metastatic GCT patients belong to the intermediate prognosis category, that was associated with a 5-year overall survival (OS) rate of 79%. However, more recent data suggest significant changes. We have thus performed an international registry of IPGCT patients to analyze current treatment, outcome, and potential prognostic factors. Methods: Data of IPGCT patients, diagnosed between 1979-2012, were retrospectively collected from 14 centers. Treatment and outcome before and after implementation of IGCCCG were analyzed. For patients diagnosed since 1997 prognostic factors were investigated by uni- and multivariate analysis to test whether current patients or subgroups may require less intensive treatment. Results: This registry includes 637 patients: group 1 diagnosed prior 1997 (n = 237), and group 2 since 1997 (n = 400). Mean follow-up duration was 128.4 months (IQR: 168.9). Patients in group 1 and 2 received first-line treatment with BEP (median 4 cycles; range 1 - 6) in 98% and 97%, respectively. Response to chemotherapy (CR and marker negative PR) was similar: 91% group 1; 94% group 2; (p = 0.233), but survival curves were significantly superior in group 2 associated with a 5-year OS rate of 87% (group 2) and 81% (group 1), respectively (p = 0.011; 95%CI 294-317). Recurrence rates were higher in group 1 (36% versus 24%; p = 0.001). Patients treated with 3 cycles BEP (n = 58) in both groups had a similar outcome concerning OS compared to patients treated with 4 cycles (n = 489) (p = 0.415). Uni- and multivariate analysis revealed LDH levels < 2.0 UNL prior chemotherapy (p = 0.018; HR 0.35) and an adequate tumor marker decline at days 18-21 (half-life) of first cycle (p = 0.025; HR 2.58) as independent prognosticators, both associated with 5-year OS rates of 94%, respectively. Conclusions: Outcome of intermediate patients seems improved after implementation of the IGCCCG classification and less intensive regimes may also be sufficient. Here, patients treated with 3xBEP had a non-inferior outcome. A baseline LDH < 2.0 UNL and an adequate tumor marker decline after first treatment cycle can be used for further stratification.
Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma (ccRCC) and its association with PD-L1 expression.
Authors: Lalani Aly-Khan A. , Albiges Laurence , Gray Kathryn P. , Pal Soumitro , Pignon Jean-Christophe , Gupta Mamta , Bhatt Rupal Satish , McDermott David F. , Atkins Michael B. , Vande Woude George Franklin , Signoretti Sabina , Choueiri Toni K.
Published: September 2018

4573

Background: Preclinical models show that c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). The relationship between c-Met and PD-L1 in human ccRCC is not well characterized. We compared c-Met expression between primary and metastatic sites in ccRCC tissues and evaluated the association with PD-L1 expression. Methods: Pairedprimary and metastatic samples from 45 ccRCC patients were included. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab, VARI) and calculated by a combined score (CS, 0-300) as: intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression was previously assessed by IHC (PMID: 26014095). c-Met expression (average c-Met CS) between paired primary and metastatic samples were compared using Wilcoxon signed-rank test. Associations of c-Met expression with PD-L1 expression (+/-) and other clinical features were assessed with Wilcoxon rank-sum tests. Results: Our cohort included 45 primary ccRCCs and 54 corresponding metastases. c-Met expression was higher in metastatic sites compared to primary (c-Met CS: 55 vs. 28, p=0.0003) and was numerically-greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression was associated with higher FNG and T-stage in both primary and metastatic sites (Table). Conclusions: Higher c-Met expression in metastases compared to paired primary tumors in our cohort of ccRCC suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. Although the observation of higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination trials. [Table: see text]
Genomic instability and DNA damage repair in clear cell renal cell carcinoma.
Authors: Pilie Patrick Glen , Zhou Lijun , Tong Pan , Matin Surena F. , Sircar Kanishka , Tamboli Pheroze , Karam Jose A. , Wood Christopher G. , Hoang Anh , Jonasch Eric
Published: September 2018

4581

Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the von Hippel Lindau gene ( VHL), in addition to nearby genes SETD2, BAP1, and PBRM. We hypothesized that VHL loss leads to defective DDR as an early event in ccRCC carcinogenesis, giving way to a mutator phenotype. We posited that assessment of very early ccRCC tumors would inform us regarding the core mutations required to drive tumorigenesis in ccRCC, and that we could confirm these findings in appropriate model systems. Methods: We performed whole-exome (WES) DNA sequencing on 11 early-stage ccRCC tumors from 5 individuals, along with their matched normal DNA. We then analyzed ccRCC samples with and without somatic VHL mutations from the Cancer Genome Atlas (TCGA) for mutational load. Finally we assessed DDR signaling activity in renal proximal tubular cell lines (RPTEC) with VHL/SETD2 knockdown and in murine embryo fibroblasts (MEFs) from Vhl and Setd2knockout mice treated with etoposide via γH2AX expression and direct repeat-green fluorescent protein reporter assay. Results: All 11 samples revealed loss of 3p with pathogenic germline or somatic mutation in remaining VHL allele. No mutations were found in genes frequently mutated in larger ccRCC, including PBRM1, BAP1 or SETD2. WES revealed ~100 mutations/tumor, with no shared mutations across samples, even within the same individual. TCGA analysis showed similar mutational loads across ccRCC samples. MEFs with biallelic loss of Vhl and monoallelic loss of Setd2 and RPTEC with VHL and SETD2knockdown displayed increased DNA damage with impaired homologous repair and increased non-homologous end joining (NHEJ). Conclusions: Early stage ccRCC tumors with loss of VHL and chr 3p demonstrate genomic instability and a mutator phenotype similar to more advanced ccRCC. Cell line models of early ccRCC show increased DNA damage with a greater reliance on error-prone NHEJ machinery. These defects could be targeted for synthetic lethal treatment strategies.
The aggressive variant prostate carcinoma (AVPC) molecular signature (-MS) and platinum-sensitivity in castration resistant prostate cancer (CRPC).
Authors: Aparicio Ana , Xiao Lianchun , Tapia Elsa Li Ning , Hoang Anh , Ramesh Naveen , Wu Wenhui , Chancoco Haidee , Heath Elisabeth I. , Efstathiou Eleni , Thompson Timothy C. , Troncoso Patricia , Broom Bradley McIntosh , Zurita Amado J. , Navin Nicholas , Logothetis Christopher , Corn Paul Gettys
Published: September 2018

5013

Background: The AVPC are a subset of prostate cancers that share the clinical, therapy response and molecular profiles of the small cell prostate carcinomas, a histological variant of the disease that responds poorly to androgen receptor directed therapies. The AVPC are characterized by a molecular signature of combined tumor suppressor defects (≥ 2 alterations in Tp53, RB1 and/or PTEN by immunohistochemistry or genomic analyses). We conducted a randomized phase II study of cabazitaxel (CAB) plus or minus carboplatin (CARB) in men with CRPC and asked whether the AVPC-MS predicted for platinum benefit. Methods: 160 men with metastatic CRPC were randomized 1:1 to receive IV CAB (25 mg/m2) or CAB/CARB (25 mg/m2; AUC4) Q21 days with growth factor support until disease progression, unacceptable toxicity or for up to 10 cycles. Imaging occurred every 2 cycles. The primary endpoint was progression free survival (PFS). 73 tumor samples obtained within 1 year of registration from 65 of the 160 patients (pts) were stained for Tp53, RB1, PTEN, AR-N terminus, AR-C terminus and Ki67. DNA of sufficient quantity for sequencing was extracted from 27 tumors and 70 plasma samples. Results: At a median follow up of 21.6 months (mo), median PFS (mPFS) in the overall population (n = 160) is 4.6 mo (95%CI 3.5, 5.8) with CAB vs 7.4 mo (95% CI 5.6, 8.3) with CAB/CARB (p = 0.004). Men with AVPC-MS-positive tumors had a mPFS of 4.5 mo (95%CI 1.5, NA) with CAB [n = 9] vs 8.0mo (95%CI 6.11-9.7) with CAB/CARB [n = 23] (p = 0.0036) whereas men with AVPC-MS-negative tumors had a mPFS of 6.8mo (95%CI 5.2, NA) with CAB [n = 12] vs 5.4mo (95%CI 3.72, NA) with CAB/CARB [n = 12] (p = 0.1445). Analysis of plasma DNA samples is ongoing and will be presented at the meeting. Conclusions: The AVPC-MS identifies a subset of men platinum-sensitive CRPC tumors. These findings should serve as the foundation for a therapeutically relevant classification of prostate cancer. Clinical trial information: NCT01505868.
Association of androgen receptor (AR) gene status in plasma DNA with outcome on enzalutamide in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Exploratory results from the PREMIERE trial—On behalf of SOGUG.
Authors: Grande Enrique , Font Pous Albert , Fernández Núñez Natalia , Gonzalez del Alba Aranzazu , Mellado Begoña , Fernandez Calvo Ovidio , Mendez Maria Jose , Climent Miguel Ángel , Duran Ignacio , Gallardo Enrique , Rodriguez Sanchez Angel , Santander Carmen , Sáez M Isabel , Puente Javier , Fernandez Perez Maria Piedad , Conteduca Vincenza , Wetterskog Daniel , Attard Gerhardt , Castellano Daniel , Gonzalez-Billalabeitia Enrique
Published: September 2018

5016

Background: Building on previous discoveries studying AR status in plasma (Carreira S, Sci Transl Med 2014, Romanel A, Sci Transl Med 2015) and following a road-map for biomarker development, we aimed to clinically qualify AR status in chemotherapy-naïve mCRPC using an optimized multiplex droplet digital PCR (ddPCR) assay (Condeduca et al.;ASCO2017;Abstract#). Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC patients were recruited in 16 Spanish hospitals. Tissue and blood samples were required at study entry. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma ARand CTC characterization (Grande E. ESMO 2016 & Font A. et al; ASCO2017; Abstract #). Outcome measures included PSA-progression-free survival (sPFS), radiographic progression-free survival (rPFS) and overall survival (OS). Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-four patients had plasma DNA available for analysis. At baseline, AR gain was present in 11 pts (12%) and CTCs in 35 (37%). AR gain in CTC-positive and negative patients was 20% and 7%, respectively. At first interim analysis and with a median follow-up of 10.6 months, detection of AR gain was associated with worse sPFS (median, 3.60 versus 15.5 m, HR, 4.33; 95% CI 1.94-9.68; P < 0.001), rPFS (median, 3.90 m versus not reached HR, 8.06; 95% CI, 3.26-19.93; P < 0.001) and OS (medians not reached, HR, 11.08; 95% CI, 2.16-56.95; P = 0.004). These results were independently associated in multivariate analysis including cfDNA and CTCs for all described endpoints. AR gain patients were less likely to have a ≥50% decline in PSA (OR, 4.93; 95% CI, 1.30-18.75; P = 0.025). Conclusions: Detection of AR gain in plasma using a robust multiplex ddPCR method predicts an adverse outcome in chemotherapy-naïve mCRPC. Further prospective randomized studies are warranted. Clinical trial information: NCT02288936.
A randomized phase II study of pelareorep (REO) plus docetaxel vs. docetaxel alone in patients with metastatic castration resistant prostate cancer (mCRPC): Canadian Cancer Trials Group study IND 209.
Authors: Eigl Bernhard J. , Winquist Eric , Tu Dongsheng , Hotte Sebastien J. , Canil Christina M. , Gregg Richard William , Zulfiqar Muhammad , North Scott A. , Ellard Susan , Ruether Joseph D. , Le Lyly H. , Kakumanu Ankineedu Saranya , Theis Ashley , Booth Christopher M. , Potvin Kylea R. , Chi Kim N. , Seymour Lesley
Published: September 2018

5021

Background: Pelareorep (REO) is an oncolytic virus with in vitro and in vivo activity in many cancers, including prostate. It has in vitro synergism with microtubule targeted agents especially taxanes. We undertook a clinical trial to evaluate REO in mCRPC patients (pts) receiving docetaxel. Methods: In this randomized, open-label multicenter phase II study, pts received docetaxel 75mg/m2 on day 1 of a 21-day cycle in combination with REO given as 3x1010 TCID50 IV daily on days 1-5 (arm A), or alone (arm B). The primary endpoint was 12-week lack of disease progression (LPD) rate. Secondary endpoints included objective response rate; survival; circulating tumor cell (CTC) enumeration at 0, 6 and 12 weeks; PSA response rate and biomarkers. Results: Eighty-five pts were randomized. Median age was 69, ECOG performance status (PS) was 0/1/2 in 31%/66%/3% of pts. Bone/regional lymph node/liver metastases were present in 98%/24%/6% of pts. More pts in arm A had poor prognostic factors for survival at baseline (median prognostic index 1.44 vs. 1.29). The median number of cycles delivered for arms A/B was 7/9 (range 1-10 and 1-13). In arm A, 51%/68% of pts received ≥90% of planned dose intensity of docetaxel/REO respectively, vs. 76% of pts for docetaxel in arm B. Adverse events (AE) were as expected for docetaxel therapy but more prevalent in arm A (grade 3 or higher all AEs 80 vs. 74%). A higher rate of grade 4 febrile neutropenia was noted in arm A (7 vs. 0%) but may represent virus related fevers. The 12-week LPD rate was 61% and 52.4% in A/B respectively (p = 0.51). OS was worse in arm A vs. B (HR 1.95; 95% CI 0.94-4.06; p = 0.07 after adjusting for age, PS and baseline prognostic score). There was no difference between arms in CTC favourable status at any timepoint. No survival benefit of REO with D was found in any subset from the biomarker analysis. Conclusions: While the combination of REO with D for patients with mCRPC was tolerable and LPD rate was comparable in both arms, docetaxel dose intensity and survival were inferior and so this combination, as tested, does not merit further study. Clinical trial information: NCT01619813.
Prognostic value of free testosterone (FT) levels during chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).
Authors: Reuter Christoph , Morgan Michael A. , Ivanyi Philipp , Grünwald Viktor , Merseburger Axel S. , von Klot Christoph A. J.
Published: September 2018

5039

Background: Carboplatin plus docetaxel (DC) may be effective in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n = 77) and during DC chemotherapy (n = 69). Results: Of the 100 pts. treated since February 2005, 96% had bone metastases, 45% had lymph node, 27% liver and 21% lung involvement. At the time of the current analysis, the median follow-up was 13.6 months, 93 pts. had died and 97 had progressive disease. The objective response rate was 36.5% in the 63 pts. with measureable disease. Response of prostate-specific antigen (≥50%) was observed in 50% of patients. Median progression-free survival (PFS) for all patients was 6.9 months (CI 95% 5.5, 8.3) and median OS was 15.4 months (CI 95% 11.5, 19.4). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (40/32%). Median free testosterone levels were 0.61 pg/ml before and < 0.18 pg/ml during carboplatin/docetaxel treatment (nadir levels, p < 0.001; detection limit < 0.18 pg/ml). Median serum androgene levels (T+DHT) were 0.1 ng/ml before and below the detection limit of < 0.05 ng/ml during DC treatment. In multivariate analyses, LDH, PSA response, free testosterone nadir levels below the detection limit ( < 0.18 pg/mL) during DC treatment were associated with longer OS (p < 0.05). Conclusions: These data suggest that carboplatin plus weekly docetaxel may be an important salvage treatment option for DRPC patients.
Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC): A phase 1/2 clinical trial.
Authors: Garcia Jorge A. , Dreicer Robert , Pantuck Allan J. , Haas Naomi B. , Vaishampayan Ulka N. , Rao Niranjan Sathyanarayana , Denis Louis J. , Tolcher Anthony W.
Published: September 2018

5041

Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase that selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction. Methods: This Phase (Ph) 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While Ph 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Ph 2. Endpoints include maximum dose (MTD) and dose limiting toxicities, recommended Ph 2 dose, PK, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 26 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, constipation and nausea. At 400mg, two pts experienced asymptomatic, reversible Gr 3 ALT/AST elevation, but no recurrence when retreated at 300mg. Enrollment of ABI/ENZA naïve patients continues at lower doses to further evaluate safety and efficacy. Testosterone decrease to below quantifiable limits and DHEA decrease of up to 80% was observed. Systemic exposure was high (Cmax, AUC and T1/2 at 300 mg QD were 6.7 µM, 80 µM.h and 21.5 h, respectively). Stable disease up to 18+ months has been observed despite prior ABI and ENZA exposure. PSA decline of > 50% (up to 93% decline) and up to 37+ wks duration was observed in 3 of 4 ABI/ENZA naïve patients at starting doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated. Prednisone co-administration was not needed. Encouraging preliminary evidence of efficacy is reflected by PSA declines in evaluable mCRPC pts not pretreated with ABI or ENZA and by durable disease stabilization in refractory disease. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.
Trop-2 expression on treatment resistant cancer cells in castrate-resistant prostate cancer (CRPC) as a predictive biomarker for targeted therapy.
Authors: Ku Kimberly Peihsi , Lang Joshua Michael , Sperger Jamie , Dehm Scott , Kohli Manish , Wang Liguo , Wang Liewei , Tagawa Scott T. , Scher Howard I.
Published: September 2018

5045

Background: Trophoblastic cell-surface antigen (Trop-2) is a transmembrane glycoprotein that is highly expressed in many solid tumors. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate of an anti-Trop-2 humanized antibody with SN-38. Early clinical trials have shown high response rates in a broad range of diseases including triple negative breast and urothelial cancers. We evaluated Trop-2 expression in tumor biopsies and circulating tumor cells (CTCs) from men with mCRPC (metastatic castrate-resistant prostate cancer). Methods: Trop-2 expression was evaluated from mCRPC biopsies from patients (Pts) treated with abiraterone acetate (AA) on the PROMOTE clinical trial, CTCs from a separate cohort treated with either enzalutamide or AA. Trop-2 CTCs were compared with EpCAM captured CTCs using a microscale technology termed the VERSA (Vertical Exclusion-based Rare Sample Analysis) platform to compare protein and gene expression signatures of resistance to these agents. Results: RNA sequencing identified Trop-2 gene expression in > 70% of metastatic biopsies. The AR splice variant V7 was found in 48 biopsies that also expressed Trop-2. Trop-2 expression was not altered by treatment with AA at 12 weeks. The number of CTCs captured from 25 pts with Trop-2 or EpCAM were closely correlated (R2= 0.84). Gene expression analysis showed similar patterns of expression for the TROP-2 and EPCAM captured cells. AR splice variant expression (AR-V7, AR-V9) in Trop-2 and EpCAM CTCs was detected in 33% of patients. Expression of neuroendocrine markers was identified in 40% of Trop-2 CTCs. Conclusions: Trop-2 is frequently expressed in mCRPC and co-expressed in tumors that express AR splice variants. Trop-2 CTCs are detected in CRPC pts previously treated with AA or Enzalutamide that also express multiple AR splice variants and neuroendocrine markers. The results support Trop-2 expression as predictive biomarker of sensitivity to targeted therapies tumors resistant to AA or Enzalutamide. Men with mCRPC are being enrolled on a Phase I trial with IMMU-132, and multi-site Phase II clinical trial in men who have progressed on AA or Enzalutamide is being finalized.
The immunomodulatory protein Dickkopf-1 (DKK1) defines a non-neuroendocrine subtype of metastatic castration-resistant prostate cancer (mCRPC) with low AR and low PSA expression.
Authors: Wise David , Armenia Joshua , Chen Yu , Nelson Peter , Schultz Nikolaus , Sawyers Charles L. , Scher Howard I.
Published: September 2018

5054

Background: Advanced stagemCRPC can manifest AR-signaling independent growth typified by loss of AR and/or PSA expression in the absence of neuroendocrine (NE) features on biopsy. We sought to identify therapeutically relevant biomarkers of this highly resistant prostate cancer subtype. Methods: An unbiased differential gene expression analysis of non-neuroendocrine mCRPC biopsies was carried out comparing patients with ARlow to patients with ARhigh disease in a discovery cohort (SU2C/PCF, 18 pts: 8 ARlow, 10 ARhigh) and validation cohort (Fred Hutchinson, 76 pts: 12 ARlow, 64 ARhigh). The AR and NE status of the biopsies were defined by AR and PSA mRNA expression and gene signatures representative of AR activity and NE lineage. An RNA sequencing-based signature of immune cell subsets was calculated using the Cibersort algorithm. Results: Differential gene expression analysis identified the secreted Wnt antagonist, DKK1, as significantly upregulated in ARlow cases compared to ARhigh cases (11.2 RPKM vs. 0.28 RPKM, p < 0.03) in our discovery cohort and confirmed in our validation cohort (9.2 FPKM vs. 0.99 FPKM, p < 0.001). DKK1 protein was also found to be increased in non-neuroendocrine ARlow relative to ARhigh prostate cancer in vitro cell and organoid models (858 pg/mg total protein vs. 2 pg/mg total protein, p < 0.05) and patient-derived xenografts (28.6 FPKM vs. 0.78 FPKM, p < 0.0001). Consistent with the role of DKK1 as a negative modulator of anti-tumor immunity, patient biopsies with the highest quartile of DKK1 expression showed an RNA signature consistent with lower levels of active NK cells (0.2% vs. 1.8%, p < 0.005), and lower levels of CD8+ T cells (3.7% vs. 9.7%, p< 0.005) compared to those with the lowest quartile of DKK1 expression. Conclusions: DKK1 represents a secreted biomarker that is disproportionately enriched in non-neuroendocrine mCRPCs that lack AR expression. Because DKK1 has been implicated as a suppressor of anti-tumor immunity and is a target of an existing neutralizing antibody, our results support the clinical evaluation of the role of DKK1 blockade in DKK1-positive AR-negative prostate cancer.
Baseline CTC subtype to predict outcomes on mCRPC patients (pts) receiving enzalutamide (E) compared to abiraterone (A).
Authors: Scher Howard I. , Jendrisak Adam , Schreiber Nicole A. , McLaughlin Brigit , Graf Ryon P , Rodriguez Angel , Fleisher Martin , Lee Jerry , Kelvin James , Wang Yipeng , Landers Mark Andrew , Dittamore Ryan Vance
Published: September 2018

5070

Background: Prior response to A or E does not predict sensitivity to E following A or A following E. The detection of AR-V7 predicts insensitivity to either drug, but identifies only a portion of non-responders. We previously identified 15 CTC subtypes based on unique phenotypic features in mCRPC pts, each with unique biology and different degree of likelihood of predicting resistance to either drug. Here we explored the relationship between individual subtypes and sensitivity to A vs. E, but not both. Methods: 107 pre-treatment blood samples from mCRPC pts starting A (n = 47) or E (n = 60) as a 1st or 2nd line of Tx were analyzed for CTCs utilizing the Epic Sciences platform. Samples were assayed for CTC subtypes based upon 15 pre-defined phenotypic CTC classifiers (Type A-O). Treatment outcomes were assessed by serial PSA changes and landmarked percent time of therapy progression on radiographs, and overall survival following either A or E. Cell type prevalence was also analyzed in relation to clinical outcomes, and subsets of the CTC subtypes subject to single cell NGS to ascertain genomic drivers common to each subtype. Results: CTCs were identified in 94% (101/107) of pt samples. One, cell Type K, found in 25% (27/107) of pts, was associated with a statistically significant inferior outcomes on E for all measures. Whereas similar outcomes were seen between K+ & K- pts treated with A. The distinct features of Cell Type K include a large nucleus, high nuclear entropy and high Nuclear/cytoplasmic AR terminal ratio; and a unique genomic profile enriched for cell cycle and DNA repair alterations relative to other CTC subtypes. Conclusions: The presence of specific CTC subtypes in pre-Rx phlebotomy samples associated with outcomes on A or E. A CTC subtype (Cell Type K) helped to identify pts with poor outcomes on E but not A vs. those without the cell type. Further biologic interrogation of K cells and ongoing clincial validation of the CTC subtype is planned. [Table: see text]
Indentification of a CTC-based gene expression signature predicting resistance to abiraterone and enzalutamide in mCRPC.
Authors: Morgan Todd Matthew , Chung Jae-Seung , Wang Yugang , Henderson James , Singhal Udit , Qiao Yuanyuan , Zaslavsky Alexander , Hovelson Daniel H , Alva Ajjai Shivaram , Feng Felix Yi-Chung , Palapattu Ganesh S. , Taichman Russell S. , Chinnaiyan Arul M. , Tomlins Scott A.
Published: September 2018

5072

Background: Circulating tumor cell (CTC)-based detection of AR-V7 has been shown to be one potential marker for predicting response to 2nd generation androgen receptor (AR) therapies. However, the apparent rarity of AR-V7 positivity is indicative of the importance of other drivers of resistance in this setting. We sought to utilize a multiplex gene expression platform for assessing CTCs in order to determine other predictive biomarkers of response. Methods: Whole blood (~5mL) was obtained from 37 patients with mCRPC starting enzalutamide (n=16) or abiraterone (n=21). CTCs were isolated using anti-EpCAM-conjugated magnetic beads. Following cell lysis, mRNA was extracted followed by multiplex qRT-PCR for 92 prostate cancer-related genes. Samples were considered CTC-positive based on a previously established set of epithelial markers. We identified genes associated with PSA and radioclinical progression free survival (PFS) using Cox regression analysis. Muli-gene models were tested using ROC analysis. Results: We identified 20 patients (54%) with detectable CTCs, and patients were followed for a median of 10 months (IQR 3.9-19.4 months). Seven genes were associated with both PSA PFS and radioclinical PFS in the Cox analyses (Table). Combing the 7 genes into a single model gave AUC values of 0.88 for PSA PFS and 0.89 for radioclinical PFS. In comparison, the AR-V7-only model resulted in AUC values of 0.65 and 0.66. Conclusions: We identified seven prostate cancer-related genes that can be determined from CTCs and appear to predict short time to progression in men with mCRPC being treated with 2nd generation hormonal therapies. While this is a small cohort and prospective validation is needed, these findings highlight the potential role for this approach in helping guide therapy choice. [Table: see text]
Neoadjuvant randomized trial of degarelix (Deg) ± cyclophosphamide/GVAX (Cy/GVAX) in men with high-risk prostate cancer (PCa) undergoing radical prostatectomy (RP).
Authors: Antonarakis Emmanuel S. , Zahurak Marianna , Schaeffer Edward M. , Partin Alan W. , Ross Ashley , Allaf Mohamad , Tosoian Jeffrey , Nirschl Thomas , Chapman Carolyn , O'Neal Tanya Skelton , Cao Haiyi , Durham Jennifer N. , Guner Gunes , Del Valle Javier Baena , Ertunc Onur , Demarzo Angelo , Drake Charles G.
Published: September 2018

5077

Background: GVAX-Prostate is a GM-CSF–secreting allogeneic cellular vaccine, whose immunogenicity may be enhanced by androgen ablation as well as low-dose Cy. We conducted a neoadjuvant immunologic study comparing Deg vs. Cy/GVAX→Deg. Methods: Men with high-risk PCa (T1c–3b N0 M0, Gleason 7–10) were randomized 1:1 to Deg(240 mg SQ) vs. Cy(200 mg/m2 IV)/GVAX(2.5×108 PC3 cells, 1.6×108 LNCaP cells) given 2 wk before Deg; all pts then had RP 2 wk after Deg. CD8+ T cell and Treg densities in the primary tumor were quantified by IHC (cells/mm2). Clinical endpoints were time-to-PSA-relapse, time-to-next-therapy, and time-to-metastasis. The study was powered (α = 0.05, β = 0.18) to show a 2-fold increase in mean CD8+ density with Cy/GVAX→Deg (Arm B) vs. Deg (Arm A). Results: 28 men were enrolled (Arm A = 15, Arm B = 13). A concurrent control group (N = 20) who did not receive neoadjuvant therapy provided untreated RP tumor samples. Baseline variables were balanced across study arms: 64% had Gleason ≥8, 56% were pT3b, 18% were pN1. There were nonsignificant increases in CD8+ and Treg densities in Arm B vs. A, and statistically significant increases in CD8+ and Treg densities in both arms (A, B) compared to group C (TABLE). CD8+ and Treg densities were strongly correlated. Outcomes were numerically better in Arm B vs A with respect to time-to-PSA-relapse (HR 0.42, 95%CI 0.13–1.38, P= 0.15) and time-to-next-therapy (HR 0.43, 95%CI 0.13–1.39, P= 0.16), although not statistically significant. Conclusions: Intratumoral immune infiltrates were marginally augmented by Cy/GVAX→Deg vs. Deg alone, while CD8+ and Treg densities were significantly greater in both study arms vs. control, supporting the immunogenic effects of androgen ablation. CD8+ / Treg ratios were remarkably consistent across groups. Clinical trial information: NCT01696877. [Table: see text]
Investigation of mechanisms of resistance to ipilimumab therapy with a pre-surgical trial in patients with high-risk, localized prostate cancer.
Authors: Gao Jianjun , Ward John Francis , Pettaway Curtis Alvin , Shi Lewis Z , Subudhi Sumit Kumar , Vence Luis M , Zhao Hao , Chen Jianfeng , Chen Hong , Efstathiou Eleni , Troncoso Patricia , Allison James Patrick , Logothetis Christopher , Wistuba Ignacio Ivan , Wargo Jennifer Ann , Blando Jorge M , Sepulveda Manuel A , Sun Jing Jing , Sharma Padmanee
Published: September 2018

5081

Background: Anti-CTLA-4 therapy ipilimumab (BMS) has led to clinical benefit in patients with metastatic melanoma. However, in multiple clinical trials in patients with prostate cancer, ipilimumab has not demonstrated significant clinical benefit. To identify potential immune inhibitory pathways responsible for resistance to ipilimumab therapy, we evaluated tumor samples from a pre-surgical clinical trial and performed correlative laboratory studies. Methods: We carried out a pre-surgical clinical trial with androgen deprivation therapy (ADT), (leuprolide acetate, Tap Pharmaceuticals) plus ipilimumab in patients with localized, high-risk prostate cancer. Each patient received one injection of leuprolide (22.5 mg) on week 0 and ipilimumab (10 mg/kg) on weeks 1 and 4. Patients then underwent surgery at week 8. Tumor tissues were collected at baseline and then at surgery for flow cytometry, IHC, multiplex immunofluorescence, and gene profiling analyses. In vitro studies were carried out for functional analysis. Results: Sixteen patients completed treatment with ipilimumab plus ADT and surgery. We observed a significant increase of immune cells including T cells and macrophages into prostate tumors after ipilimumab therapy, similar to data observed in ipilimumab-treated melanoma samples. However, compared to melanoma tumors, we found higher expression of PD-L1 and VISTA inhibitory molecules on CD68+ macrophages in prostate tumors. Interestingly, PD-L1 and VISTA were expressed on distinct subset of CD68+ macrophages, with high expression of CD163, suggesting an M2 subtype. In vitro studies demonstrated that engagement of PD-L1 and/or VISTA pathways inhibited T cell responses. Co-culture with monocytes resulted in suppression of T cell function, which can be reversed with anti-VISTA blocking antibody. Conclusions: These data suggest that evolving compensatory inhibitory pathways including PD-L1 and VISTA may mediate resistance of prostate cancer to ipilimumab therapy. Concurrent blockade of other immune checkpoints such as PD1/PD-L1 and/or VISTA may be necessary to provide significant clinical benefits for patients with prostate cancer. Clinical trial information: NCT01194271.
Refined estimates of local recurrence risks and the impact of the DCIS score adjusting for clinico-pathological features: Meta-analysis of E5194 and Ontario DCIS cohort studies.
Authors: Rakovitch Eileen , Gray Robert James , Baehner Frederick L. , Miller Dave P. , Sutradhar Rinku , Crager Michael , Gu Sumei , Nofech-Mozes Sharon , Badve Sunil S. , Hanna Wedad , Hughes Lorie L. , Wood William C. , Paszat Lawrence Frank , Shak Steven , Sparano Joseph A. , Solin Lawrence J.
Published: September 2018

528

Background: Better tools are needed to estimate the risk of local recurrence (LR; DCIS or invasive) after breast-conserving surgery (BCS) for DCIS to inform treatment decisions. The DCIS Score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS Cohort (ODC) after BCS without radiation (Solin,2013; Rakovitch,2015). We performed a meta-analysis (MA) combining data from E5194 and ODC with additional follow-up from E5194 adjusting for pertinent clinico-pathologic factors to provide refined prediction estimates of LR risk after BCS alone. Methods: The MA used data from E5194 and ODC. Patients with positive margins and multifocality were excluded. Identical Cox regression models were fit including age at diagnosis ( < 50, ≥50 yr), tumor size (1cm, > 1cm), DCIS Score and year of surgery (before vs after 2000). Grade was not significant. MA was used to calculate precision-weighted estimates of 10 year LR risk by DS. Results: Combined cohort includes 773 pts (tamoxifen used in 20% E5194, 17% of ODC > 65 yr). The DS and the clinico-pathologic variables age, tumor size and year provided independent prognostic information on 10 yr LR risk (p≤.009). Hazard ratios from E5194 and ODC cohorts were similar for tumor size ≤1 vs. > 1cm (1.45, 1.47), age ≥50 vs. < 50 yr (0.61, 0.84) and surgery year after 2000 (0.67, 0.49). 10 yr LR risks by combinations of age, tumor size, and DS are detailed in Table. For patients ≥50 yr with tumors ≤1cm and low risk DS, the 10 yr LR risks range from 5.3-10.0%. A high risk DS is associated with a higher 10 yr predicted risk of LR in all subsets. 10 yr risk of contralateral BC was 5.4%. Conclusions: This MA provides refined estimates of 10 yr LR risk after BCS alone for DCIS. Adding clinico-pathologic factors to the DCIS Score provides enhanced prognostic LR risk estimates to guide individualized treatment decision-making. [Table: see text]
A propensity score analysis exploring the impact of adjuvant chemotherapy (aCT) in a multi-center series of resected early stage pure invasive lobular breast carcinoma (ILC).
Authors: Carbognin Luisa , Sperduti Isabella , Arpino Grazia , Dieci Maria Vittoria , Schettini Francesco , Griguolo Gaia , Guarneri Valentina , Brunelli Matteo , Nortilli Rolando , Fiorio Elena , Parolin Veronica , Pilotto Sara , Orvieto Enrico , Manfrin Erminia , Pellini Francesca , Pollini Giovanni Paolo , Conte Pier Franco , De Placido Sabino , Tortora Giampaolo , Bria Emilio
Published: September 2018

539

Background: Patients (pts) resected for early breast cancer are assigned to receive aCT according to international guidelines based upon immunophenotype and clinical/pathological features, regardless of the histotype, given the lack of prospective data for ILC. Thus, the magnitude of the benefit of aCT for ILC is still not sizable. The aim of this analysis was to investigate the effect of aCT in a multi-center series of early stage pure ILC. Methods: Clinical-pathological data of consecutive pts affected by pure ILC, undergone surgery at 3 Italian institutes, were correlated with disease-free and overall survival (DFS/OS) using a Cox model. A propensity score analysis was performed to evaluate the prognostic impact of aCT. Kaplan-Meier curves were compared with Log-Rank analysis. Results: Data from 739 pts were gathered (median age 57 years (yrs); Luminal/Triple-Negative/HER2 pos.: 98%/1.6%/0.4%). At median follow-up of 78 months, 5-/10-yrs DFS and OS were 79.4%/66.0% and 91.4%/76.5%, respectively. Tumor-size according to TNM (T, HR 1.34, 95% CI 1.04-1.72, p=0.025) and lymph-node (N) status (HR 2.39, 95% CI 1.47-3.89, p<0.0001) were independent predictors for DFS at multivariate analysis. T (HR 1.87, 95% CI 0.99-3.54, p=0.05), N status (HR 3.24, 95% CI 1.69-6.22, p<0.0001), Ki67 (HR 2.48, 95% CI 0.95-6.42, p=0.06), and age (HR 2.23, 95% CI 1.16-4.30, p=0.016) were predictors for OS. A significant prognostic effect of aCT upon OS was found after adjusting for independent factors with the propensity score method, as shown in the table below. Particularly, aCT significantly prolongs OS and DFS in pts with T >1, with an absolute difference of 17%/35% and 15%/13% at 5 and 10 yrs, respectively ( p=0.003 and p=0.04). OS was longer for pts with positive N ( p=0.02), Ki67 >4% ( p=0.01) and grading >1 ( p=0.01). Conclusions: Despite the retrospective nature of this analysis, the propensity score analysis indicates that pts with ILC may significantly benefit from aCT in terms of long-term survival, particularly for larger and more aggressive tumors. [Table: see text]
An NCDB analysis of trends in male breast cancer from 2004-2009 and 2010-2014.
Authors: Dubrovsky Esther , Schwartz Shira , Chun Jennifer , Guth Amber , Axelrod Deborah M. , Shapiro Richard L. , Schnabel Freya Ruth
Published: September 2018

544

Background: To examine the trends in clinicopathologic features, treatment, and survival of male breast cancer (MBC), utilizing the National Cancer Data Base (NCDB). Methods: MBC patients entered in the NCDB from 2004-2009 were compared with those from 2010-2014 for demographics, stage at diagnosis, tumor characteristics, treatment type, and overall survival (OS). Male patients were also compared to female patients from the same time periods. Statistical analysis included Pearson’s chi-square test. Results: Of 2,047,868 breast cancer cases, a total of 19,409 (0.95%) men were available for analysis. The group of MBC patients from 2004 to 2009 included 9,790 men with a median age of 65. The group from 2010 to 2014 included 9,619 men with a median age of 66. In the later group there was a decreased rate of DCIS, increased rate of invasive ductal carcinoma, and increased rate of hormone positive tumors. Among the earlier and later MBC groups, 24% vs. 27% of patients underwent lumpectomy. Of these, 61% vs 68% received post-lumpectomy radiation, respectively. Patients in the later group (2010-2014) were more likely to receive adjuvant hormonal therapy (61% vs. 84%, p < 0.0001). MBC patients were older than female patients (65 vs. 61 years, p < 0.0001), had larger tumors (20mm vs. 16mm, p < 0.0001), slightly later stage at diagnosis, and more likely to undergo mastectomy (74 vs. 42%, p < 0.0001). MBC patients also had higher rates of hormone positive tumors, but lower rates of adjuvant hormonal therapy (55% vs. 58%, p < 0.0001). The OS for male vs. female patients in the 2004-2009 groups was 66% vs. 77% (median follow-up 73.9m vs 80.4m) respectively. Similarly, in the 2010-2014 groups, survival was 84% vs. 90% (median follow-up 33.85m vs 35.91m), respectively. Conclusions: Although men have higher rates of hormone positive tumors, they are less likely to receive adjuvant hormonal therapy. There was a significant trend over time towards more standard therapies in men, such as post-lumpectomy radiation and hormonal therapy use. There has been an improvement of OS in men which mirrors that in women. The disparities in outcomes between male and female patients, however, still require further investigation.
Breast Cancer Index (BCI) prognostic and predictive classification in older versus younger patients with early-stage HR+ breast cancer (BC) and correlation with clinical risk factors.
Authors: Yuan Yuan , Cao Yu , Israel Mason , Liu Junmei , Schnabel Catherine A. , Hurria Arti
Published: September 2018

546

Background: Older patients with HR+ BC may present distinct challenges for treatment decision-making. BCI is a validated gene expression assay for pts with early stage HR+ BC that provides 2 results: BCI Predictive, based on HoxB13/IL17BR (H/I ratio), reports a prediction of likelihood of benefit from extended endocrine therapy (EET); BCI Prognostic, based on the combination of H/I and proliferation-based genes, reports individualized risk of late distant recurrence (DR). Here, the predictive and prognostic value of BCI results across the aging spectrum ( < 64y, 65-74y, ≥75y) and correlation with clinical risk factors were examined. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains > 50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N = 14,463). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Chi-squared tests were used to compare BCI results between age groups and clinical subsets. Results: Analyses included LN- pts (N = 3,395): median age 59.1y; 5.5% ≥75y (N = 188), 24.0% 65-74y (N = 814), 70.5% ≤64y (N = 2,393). BCI Prognostic had a wide distribution of individual risk assessments in all age groups. The proportion of pts classified as high risk was similar between age groups (48.4%, 48.4% and 49.8% in ≥75y, 65-74y and ≤64y; p = 0.76). The proportion of pts with high risk results increased with increasing tumor size and grade in all age groups (P < 0.05 for all). Notably, in pts ≥75y, BCI identified 31.9% of T1a/b and 21.1% of Grade 1 tumors as high risk of late DR. BCI Predictive (H/I) also identified similar proportions as High H/I across age groups (42.0%, 41.8%, and 40.6% in ≥75y, 65-74y, and ≤64y; p = 0.81). Similar proportions of pts ≥75y were identified as high H/I across size and grade subsets (P = 0.702, P = 0.193, respectively). Conclusions: BCI identifies pts with high risk disease and who may benefit from EET across the aging spectrum. Individualized decisions for EET also must include life expectancy, competing comorbidities and potential toxicities from therapy.
Health-related quality of life (HRQOL) and patient-centered outcomes with maintenance olaparib compared with placebo following chemotherapy in patients with germline (g) BRCA-mutated (m) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): SOLO2 phase III trial.
Authors: Friedlander Michael , Gebski Val , Gibbs Emma , Bloomfield Ralph , Hilpert Felix , Wenzel Lari B. , Joly Florence , Eek Daniel , Rodrigues Manuel , Clamp Andrew R. , Penson Richard T. , Provencher Diane M. , Korach Jacob , Huzarski Tomasz , Vidal Laura , Salutari Vanda , Scott Clare L. , Nicoletto Maria Ornella , Tamura Kenji , Pujade-Lauraine Eric
Published: September 2018

5507

Background: The median PFS after chemotherapy in PSR SOC is less than 6 months in many patients. In SOLO2 (ENGOT Ov-21; NCT01874353), maintenance olaparib (O) given after response to chemotherapy resulted in a significant improvement in PFS vs placebo (P) in patients with g BRCAm PSR SOC (hazard ratio [HR] 0.30, 95% CI 0.22, 0.41; P<0.0001; median 19.1 vs 5.5 months; 63% data maturity; Pujade-Lauraine et al. SGO 2017). Our a priori hypothesis was that maintenance therapy with O would not negatively impact HRQOL compared with P and would be associated with additional patient-centered benefits to support the prolongation of PFS, the primary endpoint of SOLO2. Methods: HRQOL was evaluated by the Functional Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI) in all 295 patients. This measures functional and physical well-being and symptoms, including adverse events. Change from baseline in FACT-O TOI score during the first 12 months was the primary HRQOL analysis (mixed model repeated measures). Secondary planned analyses included duration of ‘good quality of life’ by time without symptoms of disease or toxicity (TWiST) and quality-adjusted PFS (QAPFS; a single measure of PFS and HRQOL outcomes). Results: There was no significant detrimental effect of O vs P on HRQOL analyzed by change from baseline in TOI score (–3.1 vs –2.9, respectively, difference (O minus P) –0.2; 95% CI –2.4, 2.1; P=0.88). There was a significant improvement for patients on maintenance O in TWiST (13.5 vs 7.2 months, difference 6.3; 95% CI 2.9, 8.6; P<0.001) and QAPFS (mean 14.0 vs 7.3 months for O and P, respectively, difference 6.7; 95% CI 5.0, 8.5; P<0.0001). Conclusions: Maintenance O did not detrimentally impact HRQOL relative to P. The significant improvement in PFS with O was associated with additional patient-centered benefits, including a longer duration without symptoms of disease or treatment toxicity and longer QAPFS. Clinical trial information: NCT01874353.