bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.
Authors: Bitzer Michael , Horger Marius , Ganten Tom M , Lauer Ulrich M , Woerns Marcus A , Siveke Jens T , Dollinger Matthias M. , Gerken Guido , Wege Henning , Giannini Edoardo G , Zagonel Vittorina , Cillo Umberto , Trevisani Franco , Santoro Armando , Montesarchio Vincenzo , Hauns Bernhard , Asche Julia , Jankowsky Rüdiger , Mais Anna , Hentsch Bernd ,   Shelter Study Group
Published: March 2020

4115

Background: Resminostat (R), an oral HDAC inhibitor, was studied in the SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) refractory to sorafenib (S). R was explored as monotherapy and within a novel resensitization approach to overcome tolerance to S by the combination of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were included in a multi-center, two-arm trial. Radiologic progression under S firstline therapy had to be confirmed by central review (RECIST) prior to study entry. A dose escalation of R (range 200 to 600 mg) combined with S (400 or 800 mg) was performed. Arm A investigated the drug combination (R+S), Arm B the monotherapy of R (600 mg). Primary objective was the progression-free survival rate (PFSR) after 12 weeks (w). Secondary objectives included safety, tolerability, tumor response, PFS, TTP, OS and the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme inhibition, histone acetylation and gene expressions in peripheral blood. Results: 50 pts were enrolled, dose escalation determined 600 mg R and 400 mg S for Arm A. Clinical activity results of 15 evaluable pts from combination treatment revealing a PFSR of 66.6% after 12 w, not all patients in Arm B already reached the 12 w staging. Most frequent AE were CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of non-hematological events mostly related to tumor disease. Plasma concentrations of both drugs correlated with administered doses and were in the expected range without obvious influence of preexisting liver disease. BM investigations revealed effective target modulation by R in both arms. Conclusions: The primary study objective was achieved for both treatment arms. R demonstrated a favorable PK, safety and tolerability profile, even in combination with S and despite preexisting liver disease, includig cirrhosis. The observed clinical activity emphazises the resensitizing activity of R by an epigenetic mode-of-action to overcome tolerance to S and warrants further development, in particular for combination therapy in both, first and second line HCC treatment.
Prevalence and prognostic significance of FGF receptor 2 (FGFR2) gene amplification in Caucasian and Korean gastric cancer cohorts.
Authors: Kilgour Elaine , Su Xinying , Zhan Ping , Gavine Paul , Morgan Shethah , Womack Chris , Jung Eun-Jung , Bang Yung-Jue , Im Seock-Ah , Kim Woo Ho , Grabsch Heike
Published: March 2020

4124

Background: Gastric adenocarcinoma is the 4th most common cancer, and many patients present with metastatic or recurrent disease. The prognosis for these patients is poor, with median survival times of 11–12 months. Hence there is a need for identification of potential new drug targets. We have determined the prevalence of FGFR2 gene amplification (FGFR2amp) and its relationship to clinicopathological parameters and survival in Caucasian (n=408) and Korean (n=356) gastric cancers (GC) and determined the overlap with HER2 or cMET gene amplification. Methods: FGFR2, HER2 and cMET gene amplification was assessed by fluorescence in situ hybridisation in GC tissue microarrays from Caucasian and Korean surgically resected gastric carcinomas. Gene amplification was defined as a gene/centromeric probe ratio of ≥2.0 after measuring at least 50 tumour cells. Results: 7% (30/408) of Caucasian and 4% (15/356) of Korean GC showed FGFR2amp, and the incidence was not significantly different between these cohorts (p=0.092). FGFR2amp was significantly associated with lymph node status in both cohorts (p<0.0007, multivariate analysis), and in the Korean cohort with diffuse-type histology, but not with depth of tumour invasion, age or gender. Patients with FGFR2amp showed significantly shorter overall survival in both the Caucasian (HR 2.37, 95% CI 1.6–3.5; p=0.0001) and Korean (HR 2.33, 95% CI 1.28–4.25; p=0.0129) cohorts, by multivariate analysis. There was no overlap between FGFR2amp and HER2 or cMET amplification in the Korean cohort, but two of twenty-six FGFR2amp Caucasian gastric tumours also showed HER2 amplification. Conclusions: This is the first study to demonstrate FGFR2amp, at a prevalence of 4% and 7%, in two large GC cohorts of Asian and Caucasian origin and that FGFR2amp is prognostic and significantly associated with lymph node metastasis. Furthermore, FGFR2amp is generally mutually exclusive with HER2 and cMET amplifications. Based on these observations, FGFR2 inhibitors warrant further investigation in the treatment of FGFR2 amplified GCs.
Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC).
Authors: Haas Naomi B. , Manola Judith , Ky Bonnie , Flaherty Keith T. , Uzzo Robert G. , Wood Christopher G. , Kane Christopher J , Jewett Michael A. S. , Atkins Michael B. , Dutcher Janice P. , DiPaola Robert S. ,   Eastern Cooperative Oncology Group
Published: March 2020

4500

Background: We performed a cardiac analysis of E2805, a well population of pts with resected high risk RCC. The objectives were to determine if pts treated with SU or SO had clinically significant decreases in left ventricular (LV) ejection fraction (EF) and to describe the frequency of clinically significant heart failure (HF). We also report the frequency of other events including (un)stable angina or myocardial infarction. Methods: EF was measured by multiple gated acquisition scan (MUGA) at baseline, 3, 6, and 12 months (mo), and end of treatment, if symptoms developed, and 3 mo after the last abnormal assessment. The primary cardiac endpoint was defined as an EF decline < the institutional lower limit of normal (ILN) that was a ≥ 16% decline from baseline, and that occurred ≤ 6 mo into therapy. Clinically significant HF was ≥ Grade 3 LV systolic or diastolic dysfunction (severe symptoms with any activity or from drop in EF responsive (Grade 3) or refractory (Grade 4) to therapy. Late LVEF events were a drop in LVEF of ≥ 16% occurring after 6 mo of therapy. Event rates on each treatment arm were calculated, with 90% exact binomial confidence intervals (CI). Results: Post-baseline MUGAs are available for 1589 of 1943 total pts accrued. 1293 pts had MUGA assessment ≥ 6 mo. 21 pts had primary events (Table). 71 pts had worst LVEF declines of ≥16% from baseline, including 52 of which occurred ≤ 6 mo from baseline, with the majority not meeting full primary event criteria. There were 11 reported grade 3 LV systolic events (5 SU, 4 SO and 2 PLC). 8 pts had cardiac ischemia possibly or probably from agent. Only one grade 4 event followed a primary LVEF event. 4 of 7 pts who began treatment with LVEF <ILN had primary LVEF events. Conclusions: In detailed followup of SU and SO use, cardiac function in pts starting with normal EF, was not impaired significantly over placebo. Ischemic events were uncommon and not clearly associated with treatment. The data demonstrate that SU or SO for adjuvant therapy will likely not cause significant cardiac toxicity. [Table: see text]
SWOG S0421: Phase III study of docetaxel (D) and atrasentan (A) versus docetaxel and placebo (P) for men with advanced castrate resistant prostate cancer (CRPC).
Authors: Quinn David I. , Tangen Catherine M. , Hussain Maha , Lara Primo , Goldkorn Amir , Garzotto Mark , Mack Philip C. , Carducci Michael Anthony , Monk J. P. , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Higano Celestia S. , Vogelzang Nicholas J. , Thompson Ian Murchie
Published: March 2020

4511

Background: The endothelin pathway has a mechanistic role in bone metastases (mets). Atrasentan (A), an endothelin receptor antagonist, has reported activity in CRPC. This trial tested the survival impact of A + docetaxel (D) vs. D+ placebo (P) in CRPC pts with bone mets. Methods: Eligible CRPC pts, stratified for progression type, baseline pain index (BPI), extraskeletal mets and bisphosphonate (BisP) use, were randomized 1:1 to D+A vs. D+P for 12 3-wk cycles. Non-progressors could continue blinded drug alone for 16 more wks. Co-primary endpoints: overall (OS) and progression-free survival (PFS). 930 pts were needed to detect a 25% increase in med OS with D+A (1-sided log-rank, α=0.025, 87% power). Results: 991/1,038 pts were eligible: med age 69, 16% non-white, 61% on BisP, 31% prior prostatectomy, 42% worst pain by BPI ≥ 4, 20% PSA only progression and 56% extraskeletal mets. Multivariate analysis of baseline prognostic factors predicting worse OS were: measurable or evaluable disease progression, high BPI and extraskeletal mets (all p<0.02). No differences in median OS, PFS, or response between arms. Toxicities were similar between arms. Most common toxicities were fatigue, dyspnea, neutropenia and anemia. Addition of A trended to worse OS in pts with visceral mets (HR=1.13 p=0.21) and better OS in those without: bone only (HR=0.86, p=0.20). 357 pts continued A or P up to 52 weeks, no OS difference was seen post-chemo for this subset (p=0.92). Conclusions: This phase III study found no benefit for the addition of A to D in CRPC. Unless specific biomarkers can stratify a population for benefit, endothelin modulators have limited future use in advanced CRPC. Further analyses will test putative surrogacy effects of PSA, serum bone markers and circulating tumor cell kinetics for OS. [Table: see text]
A validated whole-blood RNA transcript-based prognostic model that predicts survival in men with castration-resistant prostate cancer.
Authors: Oh William K. , Kantoff Philip , Scher Howard I. , Magidson Jay , Wassmann Karl , Lee Gwo-Shu Mary , Katz Leah M. , Subudhi Sumit Kumar , Anand Aseem , Fleisher Martin , Galsky Matt D. , Ross Robert W
Published: March 2020

4516

Background: Survival for patients with castration resistant prostate cancer (CRPC) is highly variable. We developed a whole blood RNA transcript-based model as a prognostic biomarker in CRPC. Methods: Peripheral blood was collected from 62 men with CRPC in a training set and from 140 patients with CRPC in a validation set on various treatment regimens. A panel of 168 inflammation and prostate cancer-related genes was evaluated using optimized quantitative polymerase chain reaction to assess biomarkers predictive of survival. A 2-class proportional hazard model was developed from time of CRPC diagnosis and time of blood draw. Results: A 6-gene model (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, CDKN1A) separated CRPC patients into two classes: higher risk men who died within 2·2 years of developing CRPC and lower risk men who lived over 2·2 years (log rank p=0·00083). The results were similar regardless of the survival time definition (CRPC diagnosis versus blood draw) and did not depend on whether they received chemotherapy in addition to hormone treatment. The model successfully validated in an independent cohort of men with CRPC (p= 0.000001·7). Conclusions: Transcriptional profiling of whole blood yields critical prognostic information in men with CRPC independent of treatment. The 6-gene model suggests possible dysregulation of the immune system, a finding that warrants further study. This model may play an important role in patient counseling, in patient stratification for clinical trials, and potentially as a predictive biomarker for immune-based therapeutic strategies.
Neoadjuvant androgen pathway suppression prior to prostatectomy.
Authors: Mostaghel Elahe A. , Nelson Peter , Lange Paul H. , Lin Daniel W. , Taplin Mary-Ellen , Balk Steven P. , Ellis William J , Penning Trevor , Marck Brett , True Lawrence D. , Vessella Robert , Montgomery Robert B.
Published: March 2020

4520

Background: Optimizing tissue androgen suppression may provide better local and systemic control of prostate cancer (PCa). Standard androgen deprivation therapy (ADT) has limited effect on tissue androgens which remain in a range which supports tumor survival. We determined whether targeting androgen metabolism using CYP17 and 5a-reductase (SRD5A) inhibitors would more effectively suppress tissue androgens and tumor volume. Methods: Open label, multicenter neoadjuvant study in men with localized PCa treated for 3 months prior to prostatectomy with zoladex and 1) avodart 3.5 mg QD; 2) avodart and casodex 50 mg QD; or 3) casodex, avodart and ketoconazole 200 mg TID. Serum and tissue androgens were measured by LC/MS/MS. Data were compared to men treated with standard ADT (LHRH agonist plus Casodex), and untreated prostatectomy tissue. The primary outcome measure was suppression of tissue dihydrotestosterone (DHT). Results: 35 men with intermediate/high risk PCa were enrolled. Tissue DHT was suppressed 30 fold (> 95%) in all groups vs. LHRH agonist/Casodex (0.92 ± 0.20 pg/mg vs. 0.03± 0.03 for all groups combined, p<0.0001). Tissue testosterone was 3-4 fold higher (consistent with SRD5A inhibition) in all treatment groups vs. LHRH agonist/Casodex (0.33 vs. 0.07 pg/mg, p < 0.05). Differences in DHT/T between groups 1 through 3 were not statistically significant. There was no correlation between tissue and serum androgens, or tissue androgen and tumor volume (p> 0.05). In subset analysis, total serum DHEA declined significantly in group 3, with free DHEA unchanged, suggesting differential effect on free and total DHEA. Pathologic complete response (CR) was seen in 2 men, and an additional 8 men had <0.2 cc of tumor, with the largest number of CR or near CR in the cohort treated with ADT, CYP17 and SRD5A inhibitor, 4 of 12 men (33%). Due to small cohort size, differences were not statistically significant. Conclusions: Addition of high dose SRD5A inhibition (with and without CYP17 inhibition) achieves prostate DHT levels 30 fold below standard ADT. In this relatively high risk population, CR or near CR was seen in 10 of 35 men receiving protocol therapy. Further suppressing the androgen receptor signaling axis may provide better local and systemic control of PCa.
Characteristics of long-term and short-term survivors of metastatic renal cell carcinoma (mRCC) treated with targeted therapy: Results from the International mRCC Database Consortium.
Authors: Xie Wanling , Choueiri Toni K. , Lee Jae-Lyun , Harshman Lauren Christine , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Yuasa Takeshi , Tan Min-Han , Rha Sun Young , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , North Scott A. , Rini Brian I. , Heng Daniel Yick Chin
Published: March 2020

4538

Background: Patients with mRCC have variable courses in terms of survival and response to targeted therapy. The patients at the two extremes of the survival spectrum need to be characterized. Methods: 2,161 patients with mRCC treated with targeted therapy were examined. 152 patients who survived 4 years or more after the initiation of targeted therapy (long-term) were compared with 218 patients who survived 6 months or less (short-term) over the same time period (2004-2007). Results: Long-term survivors had fewer poor prognostic factors (PFs) such as Karnofsky performance status (KPS) <80%, diagnosis to treatment interval<1 yr, hypercalcemia, anemia, thrombocytosis and neutrophilia (all p<0.0001). Patients with favorable prognosis who responded to targeted therapy were more likely to be long term survivors. For those in the intermediate risk group, patients who were long-term survivors were more likely to have only 1 poor prognostic factor (73% vs. 28%, p<0.0001) and KPS≥80% (88% vs. 69%, p=0.009) compared to those in the short term survivor group. On multivariable analysis adjusting for PFs, response to targeted therapy (PR or better) significantly predicted long term survivor status (odds ratio=6.3, 95% CI: 2.3,17.4, p=0.0004). Conclusions: Long term survivors had a higher response rate to targeted therapy, a longer treatment duration and more use of second-line targeted therapy. Baseline prognostic criteria may be able to discriminate between long- and short- term survivors. [Table: see text]
SWOG 0421: Prognostic and predictive value of bone metabolism biomarkers (BMB) in castration resistant prostate cancer (CRPC) patients (pts) with skeletal metastases treated with docetaxel (DOC) with or without atrasentan (ATR).
Authors: Lara Primo , Ely Benjamin , Quinn David I. , Tangen Catherine M. , Gertz Erik , Mack Philip C. , Twardowski Przemyslaw , Vogelzang Nicholas J. , Hussain Maha , Thompson Ian Murchie , Van Loan Marta
Published: March 2020

4547

Background: S0421, a phase III study of DOC +/- the endothelin antagonist ATR in CRPC pts with bone metastases, showed no overall survival (OS) benefit for DOC+ATR. While BMB may have a prognostic role in CRPC, their predictive role vis a vis bone-targeted therapy such as ATR is unknown. We prospectively assessed pre-treatment serum BMB from S0421 pts to validate their prognostic and predictive value. Methods: BMB for resorption (N-telopeptide, NTX and Pyridinoline, PYD) and formation (C-terminal collagen propeptide, CICP and bone alkaline phosphatase, BAP) were assayed [Quidel (PYD, CICP, BAP) and Wampole (NTX)]. Cox regression models for OS based on BMB adjusted for clinical variables were developed. An adjusted Cox model was fit with main effects and BMB x Treatment interaction to assess predictive value of ATR on OS. Results: Of 1,038 pts, 855 (82%) submitted baseline serum: 778 (91%) were usable and analyzable. Pt characteristics: median age = 69 years; PS 0-1 = 91%, Bisphosphonate use = 61%; Gleason >7 = 56%; median PSA = 68; and bone mets only = 45%. BMB values (median; range): NTX (14 nM; 9.3-23.9), BAP (64.7 u/L; 35-164), CICP (9.5 ng/mL; 6.5-17.4), and PYD (2.8 nmol/L; 2.2-3.9). Table below shows prognostic role of BMB. Pts with very high BMB (upper 25 %ile, n=47) not only have poor prognosis (HR = 4.3, p<0.001) but have OS benefit from ATR (HR=0.34, median OS = 13.6 vs. 6.7 months; interaction p=0.002**). Conclusions: S0421 validates the strong independent OS prognostic value of BMB in CRPC. Very high BMB levels appear to be significantly predictive of OS benefit with ATR. Further study of endothelin antagonists in CRPC should focus on this high-risk pt subset. (5R01-CA120469) [Table: see text]
Association of metabolic syndrome with poorer prostate cancer and overall survival in men receiving androgen deprivation therapy (ADT) for biochemical relapse.
Authors: Rudman Sarah Maria , Gray Kathryn P. , Kasperzyk Julie , Giovannucci Edward , Pitt Michael , Loda Massimo F. , Mucci Lorelei , Sweeney Christopher
Published: March 2020

4555

Background: The metabolic syndrome (MS) has been implicated in the development of prostate cancer (PC). In our previous study of a Veterans’ Administration (VA) cohort, MS was associated with a shorter duration of PC control with ADT. We report the impact of MS on overall survival (OS) and PC specific death for a cohort of patients with biochemical relapse. Methods: 273 pts (64 VA pts and 209 pts from Health Professionals Follow up Study) treated with ADT for biochemical recurrence post radiation or prostatectomy for PC were included. The modified Adult Treatment Panel III criteria for MS was used to identify patients with MS status prior to the commencement of ADT. Cox models tested for association of MS status with OS or time to PC specific death. With 42% overall death rate, 31% MS prevalence, there was 90% power to detect HR= 1.81 (type I error rate =0.05). Results: 31% pts (84/273) had MS and 15% pts (40/273) died of PC. Median follow-up was 9.5 years. The median OS with and without MS was 7.4 and 11.2 years respectively. Patients with hypertension, being African American, having diabetes and age were associated with increased risk of death from any causes, while hypertension and being African American were also associated with increased risk of PC specific death. A multivariate Cox regression model adjusted for age at diagnosis, race, definitive local therapy (RT vs. RP), PSA at diagnosis and Gleason score revealed MS was associated with a significantly increased risk of death from any cause and PC specific death (Table). Conclusions: In men receiving ADT for biochemically recurrent androgen dependent PC, the presence of MS at the commencement of ADT is associated with an increased risk of death from any cause as well as prostate cancer specifically. [Table: see text]
Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus leuprolide acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): Preliminary results of a randomized preoperative study.
Authors: Efstathiou Eleni , Davis John W. , Troncoso Patricia , Titus Mark Anton , Hoang Anh , Wen Sijin , Zurita Amado J. , Tran Namphuong , Molina Arturo , Logothetis Christopher
Published: March 2020

4556

Background: Endocrine to “intracrine” androgen signaling transition, a milestone in the lethal progression of PCa, has not been characterized in localized high risk disease. Signaling heterogeneity under the selective pressure of castration may account for response differences. Methods: A single institution preoperative study of 12 weeks AA 1g/prednisone 5 mg + LHRHa compared to LHRHa (randomized 2:1) was conducted in patients (pts) with high risk PCa (clinical stage ≥T1c and biopsy Gleason score ≥8, or ≥T2b, Gleason ≥ 7 and PSA > 10ng/ml). Primary aim: Assess difference in down staging (≤ ypT2) and safety. Secondary aims: Assess difference in androgen biosynthesis, androgen signaling (AR, AR variants, NKX 3.1, ERG, PSA) proliferation apoptosis and candidate treatment resistance pathways. Results: We report on 37 (50 enrolled) pts who had prostatectomy. AA+LHRHa was given to 25pts, LHRHa to 12. Median age is 61 ys (46-74). Preoperative PSA was <0.1ng/ml in 17/25 (68%) AA+LHRHa vs 0/12 LHRHa (p 0.0001). ypT2N0 occurred in 15/25 (60%) AA+LHRHa treated pts vs 4/12 (33%) LHRHa (p 0.17). Near complete cytoreduction (<6mm scattered cells) occurred in 6/25 (24%) AA+LHRHa vs 1/12 (8%) LHRHa. Lymph node infiltration in 7/25 (28%) AA+LHRHa vs 6/12 (50%) LHRHa. Margin positivity in 2/25 (8%) AA+LHRHa vs 4/12 (33%) LHRHa (p 0.07). Grade 3 AA related AEs: elevated AST/ALT 4 (discontinued AA), hypertension 3. One AA+LHRHa pt had postop pulmonary embolism. Androgen signaling and proliferation suppression is more profound in AA+LHRHa treated remaining tumor cells (Table). Conclusions: Addition of AA to LHRHa results in greater cytoreduction, suppression of PSA and androgen signaling compared to LHRHa in high risk PCa. Findings support the hypothesis that intracrine androgen signaling is a therapy target in patients with untreated PCa and form the foundation for a marker driven treatment strategy. [Table: see text]
Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Goodman Oscar B. , Chi Kim N. , Molina Arturo , Logothetis Christopher , Jones Robert J. , Staffurth John , North Scott A. , Vogelzang Nicholas J. , Saad Fred , Mainwaring Paul N. , Harland Stephen John , Li Jinhui , Kheoh Thian San , Haqq Christopher M. , Scher Howard I. , Fizazi Karim
Published: March 2020

4558

Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen production. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a randomized double blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To further evaluate primary survival result robustness, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS. Results: At randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); remainder discontinued D after completing all planned cycles (37%), due to toxicity (12%), or for other reasons (5%) per investigator. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD, or for all other reasons. Conclusions: These exploratory analyses suggest that the OS benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in AA arm of this study had a prolonged median OS of > 32 mos from time of initial D therapy. Congruity among these analyses and lack of dependence on D timing demonstrate robustness of the primary survival result. [Table: see text]
The effect of PSA frequency and duration on PSA doubling time (PSADT) calculations in men with biochemically recurrent prostate cancer (BRPC) after definitive local therapy.
Authors: Paller Channing Judith , Xie Sherlly , Olatoye Dare , Denmeade Samuel R. , Eisenberger Mario A. , Antonarakis Emmanuel S. , Carducci Michael Anthony , Rosner Gary L.
Published: March 2020

4559

Background: The prognostic nature of PSADT in men with BRPC makes it an attractive intermediate endpoint for assessing novel therapies in these patients. Although a number of investigational agents appear to favorably modulate PSADT, slowing in PSADT has also been observed in placebo-treated men. We aimed to determine whether PSADT calculations could be influenced by the frequency and duration of PSA measurements. Methods: We performed a retrospective analysis of men with BRPC who chose to defer hormonal therapy. Eligible men were those with PSA values ≥0.2 ng/mL and at least 6 values taken on average 3 mo apart, and whose local prostate cancer therapy was completed ≥1 year prior. To examine the influence of PSA frequency and duration on PSADT, we calculated median PSADT using different subsets of available PSA values (e.g. each vs every other; and first 3 vs. remaining PSA values). Results: After a median follow-up of 58 mo (range, 6-185 mo), 213 men with BRPC had ≥6 PSA values and 127 men had ≥9 PSA values for analysis. Men (77% white, 23% black/other) had a median age of 61 y with Gleason score distribution as follows (≤6: 30%; 7: 40%; ≥8: 18%; NOS: 12%). For men with ≥6 data points: PSADT calculated using earlier values ranged from 13.2 to 16.6 mo, compared to 16.6 to 17.8 mo, respectively, for the remaining values (within-patient change range: 0.6-1.2 mo). For men with ≥9 data points: PSADT calculated using earlier values ranged from 15.3 to 19.9 mo compared to 22.1 to 22.3 mo, respectively, for the remaining values (within-patient change range: 3.5 to 4.5 mo). When we examined the frequency of PSADT by using every other value, we found little difference (22.3 vs 22.1 mo). Conclusions: These data show that PSADT appears to increase even in the absence of therapy, and may be influenced by duration of PSA follow up. This finding explains PSADT slowing on placebo arms and calls into question the utility of PSADT as a surrogate endpoint. Placebo-controlled trials and the use of standard clinical endpoints are recommended to screen novel agents in men with BRPC to mitigate bias because of natural PSADT variability.
Gene expression biomarkers to predict overall survival of prostate cancer patients.
Authors: Li Chunde , Peng Zhuochun , Skoog Lambert , Hellborg Henrik , Jonstam Gustaf , Wingmo Inga-lill , Hjelm-Eriksson Marie , Harmenberg Ulrika , Ährlund-Richter Lars , Pramana Setia , Pawitan Yudi , Nistér Monica , Nilsson Sten
Published: March 2020

4561

Background: Current clinical parameters are not accurate in the prediction of overall survival of prostate cancer patients. Methods: Driven by cancer stem cell hypothesis and by using a simple bioinformatics analysis, we identified 641 genes with either consistently high or low level of expression in human embryonic stem cells. We showed that these 641 genes had strong power to classify cancers into different biological subtypes and named them as embryonic stem cell gene predictors (ESCGPs). Nineteen selected ESCGPs and five control genes were analyzed by multiplex quantitative PCR in prostate fine needle aspiration (FNA) samples taken at diagnosis. The cohort included 189 patients diagnosed during 1986-2001. Of these patients, 97.9% had overall and cancer specific survival data and 77.9% were treated by medical or surgical castration as the primary treatment. The cohort was divided into a discovery and two validation subsets. The univariate and multivariate Cox proportional hazards and Kaplan-Meier plots were used in the survival analysis. A published dataset was used for an external validation. Results: Ten gene markers F3, WNT5B, VGLL3, CTGF, IGFBP3, c-MAF-a, c-MAF-b, AMACR, MUC1 and EZH2, showed a significant correlation to overall or cancer specific survival. Four of these genes, F3, IGFBP3, CTGF and AMACR, were independent of all clinical parameters. An expression signature of F3, VGLL3 and IGFBP3 characterized patients into three subtypes. The median overall survival was 2.60 years in the high risk, 3.85 years in the intermediate risk and 7.98 years in the low risk subtype, corresponding to a HR of 5.86 (95% CI 2.91-11.78, p<0.001) for the high risk and 3.45 (95% CI 1.79-6.66, p<0.001) for the intermediate risk over the low risk subtype. Two gene markers, F3 and EZH2, were further verified by the external validation. Conclusions: The new ESCGP gene markers and the expression signatures can be used to predict the overall and cancer specific survival of prostate cancer patients.
Generation of a prognostic cancer stem-like gene expression signature in men undergoing radical prostatectomy for localized prostate cancer.
Authors: Fairey Adrian Stuart , Yang Dongyun , Groshen Susan G. , Quinn David I. , Kim Philip , Virk Navneet , Wang Lina , Martin Sue Ellen , Stephens Craig , Goldkorn Amir
Published: March 2020

4563

Background: Novel biomarkers are needed to predict recurrence after radical prostatectomy for localized prostate cancer. Recent data suggest that cancer stem-like cells (CSC) are present in prostate tumors, and the CSC phenotype has been associated with an aggressive cancer phenotype. We investigated whether tumor mRNA levels of genes typically expressed by CSC are associated with disease recurrence. Methods: Clinically annotated prostatectomy specimens (FFPE) were used for this nested case-control study. Samples represented men who underwent radical prostatectomy and either experienced a recurrence (PSA or clinical; n=152) or no recurrence (controls; n=124) with minimum 5-year follow-up. Men were excluded if they received neoadjuvant hormone therapy. Cases and controls were frequency matched based on D’Amico risk group. Laser capture microdissection with mRNA extraction and quantitative RT-PCR were used to quantify the expression of 12 candidate CSC-associated genes (ALDH1A1, Axin2, Bmi1, CD133, CD44a, CTNNB1/β-catenin, ITGA2/integrin α2, NANOG, Nkx3-1, Notch1, OCT 4, TACSTD2/Trop2). Univariable and multivariable analyses were conducted to measure associations with recurrence. Results: mRNA data were evaluable for 241 of 276 patients. Univariate Wilcoxon analysis showed that 4 genes (Axin2, p<0.001; CD44a, p=0.036; OCT 4, p=0.017; TACSTD2, p=0.008) were expressed at low levels in tumors of patients whose disease recurred. Recursive partitioning analysis identified 3 genes significantly predictive of disease recurrence (Axin2, NANOG, CTNNB1), with cutpoints yielding odds ratios (OR) of 8.5 (Axin2low/NANOGhigh; n=94, 95%CI 3.7-19.2) and 5.1 (Axin2low/NANOGvery high/CTNNB1low; n=26, 95%CI 1.7-14.8). Conclusions: We identified a novel CSC-associated 3 gene expression signature with the potential to predict recurrence after radical prostatectomy. Axin2 is known to interact with CTNNB1/β-catenin in the Wnt signaling pathway, which in turn has been shown to regulate expression of NANOG, a key protein that mediates pluripotency. In vitro experiments and an independent cohort validation study are planned based on these novel findings.
Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.
Authors: Lee Richard J. , Michaelson M. Dror , Saylor Philip James , Gurski Carol Ann , Rothenberg Stephen M. , Miyamoto David Tomoaki , Maheswaran Shyamala , Haber Daniel A. , Goldin Jonathan G. , Smith Matthew Raymond
Published: March 2020

4566

Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to <5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.
A multinational phase III adjuvant study of immediate (I) versus deferred (D) chemotherapy (C)/hormone therapy (HT) after radical prostatectomy (RP): TAX-3501.
Authors: Eisenberger Mario A. , Kattan Michael W. , Sternberg Cora N. , De Wit Ronald , Epstein Jonathan I , Ecstein-Fraïssé Evelyne B , Kibel Adam Stuart
Published: March 2020

4570

Background: TAX 3501 was designed to test I or D C/HT after RP. No adequately designed prospectively randomized surgical systemic adjuvant studies have ever been successfully completed. Methods: TAX-3501 was a randomized phase III study. Eligibility included post-operative predicted probability of 5-year freedom from progression of <60% (Kattan et al) after central pathology review, no prior C/HT, undetectable PSA, M0, normal hematology/chemistries, signed consent. Pts were randomized within 120 days after RP to I or D (at 1st progression) Rx with HT (leuprolide acetate 22.5mg S.C. q.3 months x 6 ) +/- C (docetaxel 75mg/m2 q.3wks x 6). F/U included a physical exam, PSA, CBC/chemical profile, serum T, scans yearly or at progression (PSA≥ 0.4ng/ml, clinical or radiographic and death). Main objectives comparing PFS and 5-year progression-free rates after systemic treatment (2 × 2 factorial design, 4 arms). 1,696 subjects would provide 90% power to detect the targeted treatment effect at a 5% 2-sided type I error level. Results: From 12/2005-9/2007399 pts were registered, 228 randomized after central path review ICHT=55, IHT=55, DCHT=56, DHT=62, median age 62 (41-76), pre-op PSA (ng/ml) 9.38 (2.2 - 90.0), Gleason score- 8,T3a (19.6%),R+(65%),S.V.+(50%),N+(19.7%%), all had undetectable post op PSA. Predicted probability of no progression was 21% on 228pts. Study was terminated by sponsor (9/2007) due to poor accrual F/U continued from 2007-2010. Small sample size precludes reliable analyzes 37/118 (31.3%) on the D arms received CHT/HT (all PSA progressions); ICHT 10/55, IHT 14/55, DCHT 9/56, DHT 8/62 met progression endpoint after I/D Rx (1/31 bone). AEs were characteristic and reversible (no grade 5). Leading causes of accrual impediment were inadequate site selection, no consensus regarding patient and treatment selection for this pt population, physician and patient bias re: treatment and evolving changes in the adjuvant treatment landscape during follow-up time (adjuvant RT). Conclusions: The role of adjuvant systemic treatment after RP remains undefined. Clinical trials in this pt population are challenging. Supported by Sanofi NCT000283062.
Multidimensional investigation of HER2 in advanced urothelial carcinoma (UC).
Authors: Park Rachel S. , Werner Lillian , Greulich Heidi , de Muga Silvia , Salido Marta , Stack Edward C. , Lis Rosina , Schutz Fabio A. B. , Lloreta Trull Josep , Gallardo Enrique , Rojo Federico , Berman David M. , Molins Joaquim Bellmunt , Rosenberg Jonathan E.
Published: March 2020

4580

Background: Incidence of Her2 positivity and association with overall survival (OS) are controversial in advanced UC. Activating Her2 mutations have been identified in other cancers, but they have not been previously reported in UC. We determined Her2 status by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and copy number gain (CNG) via array CGH of primary UC tumors from patients (pts) with metastatic disease. Targeted Her2 sequencing was performed at known mutation hotspots, and mutation effect was investigated in vitro. Methods: Tissue microarrays of formalin fixed paraffin-embedded tumor from 98 UC pts treated with platinum-based combination chemotherapy for metastatic disease were evaluated for Her2 protein and for Her2 gene amplification by using standard clinical protocols. Positive staining was defined as an IHC score of 3+ or a FISH ratio of ≥2 using scoring criteria established for evaluation of breast cancer. Her2 CNG was evaluated by aCGH with cutoff log base 2 ratio > 0.9. Mutation status was validated by hME sequencing. OS was measured from start of treatment for metastatic disease. Association of OS and Her2 status was assessed by a Cox regression model. NIH-3T3 cells with Her2 V777L were assessed for growth, invasion, and Her2 kinase activation. Results: 22% of pts had 3+ Her2 staining by IHC. 21% of pts had FISH amplification. These were concordant in 78% of pts. CNG was identified in 16% and was concordant with FISH and IHC 85% and 88% of the time, respectively. Her2 status by any modality showed no significant association with OS in either univariate [HR=0.94, 95% CI: (0.52, 1.70), p=0.83] or multivariate [HR=1.12, 95% CI: (0.61, 2.06), p=0.72] analysis. Her2 mutations (V777L and L755S) were identified in 2 pts (2%). In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and Her2 kinase constitutive activation. Conclusions: Her2 overexpression or amplification in the primary tumor does not predict OS in pts with metastatic UC. Other research has suggested that V777L sensitizes cells to lapatinib, while L755S leads to lapatinib resistance. These rare oncogenic Her2 mutations occur and may be therapeutic targets in selected pts.
Mortality from other malignancies in bladder cancer survivors.
Authors: Ahmadi Hamed , Skinner Eila C. , Miranda Gus , Cai Jie , Djaladat Hooman , Leslie Scott , Daneshmand Siamak
Published: March 2020

4589

Background: Other-cause mortality represents a considerable proportion of overall long-term mortality in bladder cancer (BC) patients who underwent curative radical cystectomy (RC). Other malignancies besides BC are reportedly among the most common etiologies of other-cause mortality. We report on mortality from other malignancies in BC survivors who have undergone prior RC. Methods: Data on BC patients who died of other malignancies were derived from a cohort of 1964 patients with pathologic diagnosis of urothelial carcinoma of bladder who underwent RC with intent to cure due to BC at University of Southern California between 1971 and 2008. For subsequently developed malignancies, the time interval between RC and occurrence of malignancy was calculated. Other malignancies mortality was evaluated with respect to gender, pathological stage of BC, and type of malignancy. Results: Other malignancies were diagnosed in 463 (23.5%) patients. They were the cause of death in 122 (6.21%) patients (109 male) who had a median age of 68.6 (range 43.4 – 88.7) at time of RC. Of all 122 patients with other malignancies, 22(18%) patients were diagnosed prior to RC, 5 (4%) concurrently with BC diagnosis, and 94 (77%) subsequent to RC. At the time of cystectomy, 87/122 (71.3%) patients had lymph node-negative organ-confined disease, compared to 56.3% in the whole cohort; and 18 (14.7%) patients had nodal disease, compared to 23.2% in the whole cohort. 116/122 (95%) of these patients had no evidence of BC recurrence at time of death. Secondary cancers occurred at a median of 7.7 years (Range 3 months – 29.9 years) after RC. Most common sites and types of malignancies that led to death were lung in 43/122 (35.2%), predominantly non-small cell carcinoma in 17/43(39.5%); hematologic in 15/122 (12.3%), largely lymphoma in 6/15 (40%); and colon in 11/122 (9%), primarily adenocarcinoma in 8/11 (72.7%) patients. Conclusions: Lung, hematologic, and colon cancers are the most common causes of death due to other malignancies in BC survivors and more commonly found in male patients with lymph node-negative organ-confined tumor. Continued screening for other cancers in the follow-up of BC survivors may be warranted.
External validation of prognostic models for overall survival (OS) in patients (pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy.
Authors: Apolo Andrea Borghese , Philips George , Ostrovnaya Irina , Rosenberg Jonathan E. , Milowsky Matthew I. , Small Eric Jay , Bajorin Dean F. , Halabi Susan
Published: March 2020

4592

Background: The most commonly used model predicting OS for UC pts treated with cisplatin-based chemotherapy is based on 2-variables (visceral metastases and performance status), developed at MSKCC in 1999, and validated in a phase III study (DeSantis JCO 2011). A prognostic model of OS for advanced UC pts based on 4 variables (visceral metastases, albumin, performance status, and hemoglobin) was developed using 308 pts from MSKCC (ASCO 2007 abstr 5055). We report the discriminative ability of the 4- and 2- variable models for advanced UC pts using an independent dataset from CALGB 90102. Methods: The analysis was performed using an external multi-institutional dataset from CALGB 90102. The primary measurement of predictive discrimination was Harrell’s c-index which was computed with 95% confidence interval (CI). To assess whether there was a statistically significant difference in discrimination between the two models, the U statistic was used to test whether the predictions of the 4-variable model in all possible pairs were more concordant with actual observations than the 2-variable model in the same pairs. Results: CALGB 90102 included 74 UC pts (58 males, 16 females), median age 64 years, treated with cisplatin, gemcitabine and gefitinib, enrolled from 7/02 to 4/05 with a median follow-up of 72.5 months. Visceral metastases were present in 64% (bone, 18%, liver, 31%, lung, 43%), median KPS 90%. The MSKCC 2-variable risk group distribution was 30% =0, 65%= 1 and 5%=2. The median OS =12.7 months (95% CI=10.4-20.5) with 68 deaths observed. When applied to the CALGB cohort, the predictive accuracy for the 4- and 2-variable models were 0.63 (95 CI= 0.56- 0.69) and 0.58 (95% CI= 0.52-0.65), respectively. There was a statistically significant difference in discrimination between the two models (p =0.019), with superiority of the 4-variable model compared to the 2-variable model. Conclusions: A 4-variable prognostic nomogram for survival in pts with advanced UC was superior to a 2-variable risk-group model. The 4-variable prognostic model may replace the widely used 2-variable model and can be used in the design and conduct of future phase II and III trials in advanced UC.
Late gastrointestinal (GI) complications in patients with stage I-II testicular seminoma treated with radiotherapy (RT).
Authors: Hallemeier Christopher Leigh , Davis Brian , Pisansky Thomas Michael , Choo Richard
Published: March 2020

4595

Background: For stage I-II testicular seminoma, RT is highly effective at eradicating disease in the abdominopelvic lymph nodes, but results in unnecessary exposure to normal tissues including the GI tract. The purpose of this study was to define the incidence and risk factors for late GI complications in this patient population. Methods: A retrospective review was performed of 251 patients with stage I-II testicular seminoma treated with curative intent RT at our institution from 1974-2009. All patients underwent orchiectomy and postoperative external beam RT to the involved and/or at-risk nodal basins. Potential late GI complications that were assessed included endoscopically-confirmed gastric or duodenal ulceration, small bowel obstruction (SBO), and biopsy-confirmed malignancy of the GI tract. Risks were estimated using the Kaplan-Meier (KM) technique and univariate/multivariate analyses were performed using the Cox proportional hazards model. Results: Median age at diagnosis was 36 years (range 18 – 80). Clinical stage was I (n=199) or II (n=52). Median abdominopelvic RT dose was 26 Gy (interquartile range 25 – 30). Median follow-up was 15 years (range 0.1 – 38). KM estimates for any GI complication (ulcer, SBO, or GI malignancy) at 10, 20, and 30 years were 7, 10 and 24%, respectively. Four patients died as result of a GI complication. KM estimates for ulcer at 10, 20, and 30 years were 4, 7, and 9%, respectively. Age at RT (Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.00 – 1.10, p=0.03) and RT total dose (per Gy, HR 1.20, 95% CI 1.09 – 1.31, p<0.01) were associated with risk of ulcer. KM estimates for SBO at 10, 20, and 30 years were 2%, 2%, and 3%, respectively. History of inflammatory bowel disease was associated with risk of SBO (HR 43, 95% CI 7-325, p<0.01). KM estimates for GI malignancy at 10, 20, and 30 years were 0.5, 3 and 16%, respectively. Age at RT was associated with risk of GI malignancy (HR 1.07, 95% CI 1.02-1.14, p=0.01). Conclusions: In patients with stage I-II testicular seminoma treated with RT, late GI complications were a relatively uncommon, but clinically significant source of late morbidity. Use of low dose, limited field, and/or proton RT may reduce these risks.