ASCO 12 Annual Meeting, June 1-5, 2012, Chicago, Illinois, USA
Castration resistance and high-risk disease among nonmetastatic (M0) prostate cancer (PC) patients
on androgen deprivation therapy (ADT).
Abstract No:1581
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 1581)
Author(s): Melissa Pirolli, Rohini Khorana Hernandez, Karynsa Cetin, Jane Quigley, Yanina Grant-Huerta,
Scott Stryker, Paul Smith, John Adams, Alexander Liede; SDI Health, Plymouth Meeting, PA; Center for
Observational Research, Amgen Inc, Thousand Oaks, CA; Amgen Inc., Thousand Oaks, CA; RAND
Corporation, Santa Monica, CA
Abstract:
Background: Prostate-specific antigen (PSA) is a well-known PC biomarker. In the M0 setting, rising PSAs
despite ADT is an indication of the development of castration-resistant prostate cancer (CRPC). In this
disease state, men are at risk for developing bone metastasis (BM), which is associated with significant
morbidity and may negatively affect survival. Using real-world data, we explored PSA-based criteria to
identify patients who develop CRPC while on ADT and the subsets that may be at increased risk of BM.
Methods: We used the Oncology Services Comprehensive Electronic Records (OSCER) database, which
includes electronic medical record (EMR) data on cancer patients from 328 urology and oncology clinics in
the US. Eligible patients were adult men with M0 PC with ≥1 PSA recorded between 3/1/2010 and 2/28/2011
and currently receiving ADT (gonadotropin-releasing hormone agonists or bilateral orchiectomy) for ≥6
months (mos). We defined CRPC as two sequential PSA rises while on ADT and high risk for BM as any
PSA ≥8 ng/mL or PSA doubling time (DT) ≤10 mos, as described by Smith MR et al, Lancet 2012. We
explored subsets of CRPC patients who may be at even higher risk of BM using PSA thresholds (≥8 ng/mL
and ≥20 ng/mL) and DT (≤4, 6, 8, and 10 mos). Results: Of 1,818 men with M0 PC receiving ADT ≥6 mos,
36% (N=646) met the CRPC definition, of whom 80% (N=517) had PSA ≥8 ng/mL and/or PSA DT ≤10 mos
(high risk). PSA DT alone explained 63% (44% / 70%) to 93% (65% / 70%) of subgroup eligibility (Table),
and emerged as a main driver in defining increased risk of BM for CRPC subsets. Conclusions: In this
analysis of EMR data, over one-third of men with M0 PC on ADT met criteria for CRPC, and most CRPC
patients (80%) may be considered at high risk for BM. Requiring ≥3 PSAs to define CRPC may be a
limitation; however, because PSAs are closely monitored in patients on ADT, these definitions of CRPC and
high risk may be useful in practice. These data suggest that PSA DT may be a more clinically meaningful
measure of defining CRPC subsets than absolute PSA thresholds.
CRPC subsets PSA ≥8 ng/mL PSA ≥20 ng/mL No PSA threshold (PSA < 8 ng/mL)
DT ≤10 mos
80%
70%
65%
DT ≤8 mos
78%
67%
60%
DT ≤6 mos
75%
63%
54%
DT ≤4 mos
70%
56%
44%
Testosterone levels as a prognostic factor for survival in patients with castrate-restistant prostate
cancer (CRPC).
Abstract No:e15159
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15159)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Alfonso Gomez de Liaño, José Pablo Maroto, Cristina Martin Lorente, Elena Cillan, Ismael
Macias, Agostina Stradella, Ivana Sullivan, Paola Murata, Cristina Arqueros, Georgia Anguera, Dhiossett
Condori, Agust Barnadas; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Abstract:
Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in
patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50
ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution
since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required
castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results:
Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was
66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic
prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping
antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of
chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85
months. For 26 patients with a serum testosterone level below the median value, median survival was 17
months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036).
Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic
factor for survival in patients with metastatic prostate cancer considered castration resistant.
Changes in prostate-specific antigen doubling time (PSADT) prior to and after treatment with
hormonal therapy (HT) in men with biochemically recurrent prostate cancer (BRPC): A preliminary
analysis.
Abstract No:e15188
Citation:
J Clin Oncol 30, 2012 (suppl; abstr e15188)
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with
the 2012 Annual Meeting but not presented at the Meeting, can be found online only.
The publication-only abstracts are not included in the print or USB versions of the ASCO Annual
Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a
supplement (see citation on left).
Author(s): Victoria J. Sinibaldi, Peng Huang, Emmanuel S. Antonarakis, Michael Anthony Carducci, Mario A.
Eisenberger; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD
Abstract:
Background: PSADT is an important prognostic parameter in all clinical states of PCA. Intra -subject
changes in PSADT prior to and after HT remains undefined. Methods: Men with rising serum PSA levels
after local therapy were longitudinally followed from the hormone-sensitive (HS) to the castration-resistant
(CR) state. PSADT was calculated according to standard formulas ( Pound et al., JAMA 1999) and
previously identified prognostic subgroups (Antonarakis et al., BJU Int 2012; Freedland et al., JCO 2007)
were used to evaluate the potential clinical significance of PSADT according to the following subgroups: [1] <
3 months (mo); [2] 3-8.9 mo, [3] 9-14.9 mo, and [4] ≥ 15 mo). Results: 55 men with BRPC who eventually
developed CR disease on HT were retrospectively analyzed. The median age of HS men was 60 y (range (r)
43-78); CR men 66 y (r 43-87). Of all men, 28 had prior surgery (S), 5 had radiation (R), 14 had S+R, 7 had
neoadjuvant /adjuvant HT + local therapy, and 1 had no local therapy. PSADT in the CR state was shorter
than PSADT in the HS state (signed –rank test; p=0 .012). HS men with PSADT < 4 m had shorter overall
survival than those with PSADT ≥ 4 mo ( 13.9 vs. 20.1 mo; HR ; 8.46). Changes in PSADT from the HS to
the CR state are summarized in the Table below. The majority of men converted from a more favorable to a
less favorable PSADT subgroup as they progressed from HS to CR states. Conclusions: PSADT tends to
shorten from the HS to the CR states. The prediction of clinical outcome based on PSADT needs to account
for the clinical state the patient is in, as PSADT may change within the same patient from state to state.
[PSADT
PSADT changes with
Baseline PSA
prognostic
HT
from the HS to CR
M+
PSADT (mo)
Subgroup
(ng/ml)
subgroups]/#men
state
#men
Median (r)
Median (r)
[1] [2] [3] [4] Better Worse
Same
HS
0/55 8.2 (0.9-65.2
4.57 (0.38-54)
13 34 5
3
n/a
n/a
n/a
2.88 (0.86CR
47/55 19 (1.2-181)
30 21 3
1
8(14%) 31 (56%) 16(29%)
16.03)
Prognostic stratification of post-docetaxel metastatic castration resistant prostate cancer (mCRPC)
from a phase III randomized trial.
Abstract No:4644
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4644)
Author(s): Guru Sonpavde, Gregory Russell Pond, Stephen John Clarke, Janette L. Vardy, S. L. Wang,
Jolanda Paolini, Mariajose Lechuga, M. Dror Michaelson, Matthew Raymond Smith, Isan Chen, Edna Chow
Maneval; Texas Oncology, Houston, TX, and Department of Medicine, Section of Medical Oncology, Michael
E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX; McMaster University,
Hamilton, ON, Canada; Royal North Shore Hospital, St. Leonards, Australia; Sydney Cancer Centre,
University of Sydney, Sydney, Australia; Pfizer Oncology, La Jolla, CA; Pfizer Inc., Milano, Italy; Pfizer
Oncology, Pfizer Italia Srl, Milan, Italy; Massachusetts General Hospital Cancer Center, Boston, MA; Aragon
Pharmaceuticals, San Diego, CA
Abstract:
Background: A prognostic model for mCRPC post docetaxel is necessary to guide therapy. We
retrospectively analyzed a phase III trial enrolling progressive mCRPC following docetaxel to construct a
prognostic model. Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a potential
marker for inflammatory and immune state. Methods: A phase III trial (SUN-1120) comparing prednisone
combined with sunitinib (N=584) or placebo (N=289) for mCRPC following docetaxel-based chemotherapy
was evaluated. The treatment arms were combined for analysis, since no statistical difference was observed
in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal
factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for
survival, we used a Cox proportional hazards regression methods with forward stepwise selection, stratifying
for ECOG PS, progression type (PSA or radiographic) and treatment group. A risk score was calculated and
patients were categorized into risk groups to assess model performance. Results: Data from patients
without missing data (n=806) were used to construct an optimal model. The factors used in the model that
remained individually significant in multivariate analysis were: log-LDH (HR 2.77 [95% CI=2.23, 3.44],
p<0.001), hemoglobin (0.81 [0.76, 0.87], p<0.001), log-NLR (1.63 [1.38, 1.92], p<0.001), >1 organ involved
(1.53 [1.24, 1.88], p<0.001), log-alkaline phosphatase (1.14 [1.01, 1.30], p=0.041) and log-PSA (1.07 [1.00,
1.13], p=0.036). No clear cutpoints were identified; thus, these prognostic factors were used to group
patients into 3 equally sized risk categories. Low, medium and high risk patients (n=268-270 per group) had
median (95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and 7.3 (6.3-8.4) months,
respectively. Conclusions: A prognostic risk model with readily available variables significantly
discriminated between outcomes in post-docetaxel mCRPC and may provide valuable information in future
studies. High NLR was associated with an independent poor prognostic impact, and warrants prospective
validation.
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).
Abstract No:4547
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4547)
Author(s): Primo Lara, Benjamin Ely, David I. Quinn, Catherine M. Tangen, Erik Gertz, Philip C. Mack,
Przemyslaw Twardowski, Nicholas J. Vogelzang, Maha Hussain, Ian Murchie Thompson, Marta Van Loan;
University of California, Davis, Sacramento, CA; Fred Hutchinson Cancer Center, Seattle, WA; University of
Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Fred Hutchinson Cancer
Research Center, Seattle, WA; USDA, WHNRC, Davis, CA; City of Hope, Duarte, CA; US Oncology
Research, LLC, McKesson Specialty Health, The Woodlands, TX, and Comprehensive Cancer Centers of
Nevada, Las Vegas, NV; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; University of
Texas Health Science Center at San Antonio, San Antonio, TX
Abstract:
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)
Median survival,
months (<= median
Biomarker
p-value*
BMB value vs.
> median)
BAP (u/l)
1.23 (1.14, 1.32) 22.8 vs. 15.4
<0.001
CICP (ng/ml) 1.38 (1.26, 1.51) 24.5 vs. 14.6
<0.001
NTx (nM)
1.40 (1.27, 1.54) 22.4 vs. 15.5
<0.001
PYD (nmol/l) 1.52 (1.28, 1.81) 22.0 vs. 15.3
<0.001
* Significance set at < 0.006 to control 2-sided error rate at 0.05. **Significance set at <0.01 to control overall
2-sided error rate at 0.05 (Bonferroni adjustment).
Hazard ratio
(95% CI)
Time to testosterone (T) and PSA rises during first “off treatment” interval (1OFF-2ON) of intermittent
androgen deprivation (IAD) as prognostic for time to castration resistance (CRPC) and prostate
cancer mortality (PCM) in men with biochemical relapse (BR).
Abstract No:4557
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4557)
Author(s): Evan Y. Yu, Kevin F Kuo, Rachel Hunter-Merrill, Roman Gulati, Suzanne P Hall, Teresa E
Gambol, Ruth D Etzioni, Celestia S. Higano; Fred Hutchinson Cancer Research Center, Seattle, WA;
University of Washington, Seattle, WA
Abstract:
Background: A recent phase III trial of intermittent vs. continuous AD supports IAD as standard of care for
men treated with AD for BR. To identify potential prognostic factors during 1OFF, times to T and PSA rises
from our prospective trial of IAD in men with BR were analyzed in relation to times to CRPC and PCM.
Methods: 72 men with BR after definitive local therapy were treated with IAD, each cycle consisting of 9
months of leuprolide and flutamide followed by a variable “off treatment” interval. T and PSA were followed
monthly; AD was resumed when PSA reached a pre-specified value. Cycles repeated until CRPC, defined
as ≥2 PSA rises with T≤50 ng/dL. Markers of interest from 1OFF-2ON were time to first T>50, time from first
T>50 to first PSA rise ≥0.1 ng/mL, time to first PSA rise ≥0.1, and PSA doubling time (PSAdt), calculated
using the first 3 PSA measurements starting from first PSA ≥0.1. The associations of these markers with
CRPC and PCM were evaluated using Cox proportional hazards models (or logistic regression if the Cox
proportional hazards assumption was not met), controlling for age at study entry and Gleason score
categorized to ≤7 or >7. Results: A 30-day increase in time to first T>50 was significantly associated with a
75% increase in the risk of PCM. A 30-day increase in time to PSA rise from 1OFF or after T>50 was
significantly associated with a 23% or 72% reduction in the risk of CRPC, respectively. While neither of the
associations of PSAdt with CRPC or PCM were significant, they were of moderate size: PSAdt displayed a
moderate reduction in risk of CRPC by 35% and PCM by 38%. Conclusions: During the first “off treatment”
interval of IAD, the time to first T>50 is prognostic for PCM. Time to first PSA rise after 1OFF and after first
T>50 are both prognostic for CRPC.
Time to CRPC
Time to PCM
Marker
N HR P value 95% CI N HR P value 95% CI
1OFF to T>50
46 1.1 0.67
(0.71, 1.7) 49 1.75 0.01
(1.14, 2.68)
T>50 to PSA≥0.1 45 0.28 0.05
(0.08, 0.99) 48 0.28 0.19
(0.03, 1.63)++
1OFF to PSA≥0.1 57 0.77 0.01
(0.63, 0.93) 60 0.85 0.24
(0.65, 1.11)
PSAdt
49 0.65 0.08
(0.4, 1.06) 52 0.62 0.29
(0.26, 1.5)
++ Odds ratio.
Gene expression biomarkers to predict overall survival of prostate cancer patients.
Abstract No:4561
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4561)
Author(s): Chunde Li, Zhuochun Peng, Lambert Skoog, Henrik Hellborg, Gustaf Jonstam, Inga-lill Wingmo,
Marie Hjelm-Eriksson, Ulrika Harmenberg, Lars Ährlund-Richter, Setia Pramana, Yudi Pawitan, Monica
Nistér, Sten Nilsson; Department of Clinical Oncology, Karolinska University Hospital, Stockholm, Sweden;
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Pathology and
Cytology, Karolinska University Hospital, Stockholm, Sweden; Regional Oncologic Center, Karolinska
University Hospital, Stockholm, Sweden; Karolinska University Hospital Hudingge, Huddinge, Sweden;
Department of Oncology-Pathology, Stockholm, Sweden; Department of Women and Children's Health,
Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska
Instiutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
Stockholm, Sweden
Abstract:
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.
Predictive biomarkers in circulating tumor cells (CTC) from patients with castration-resistant
prostate cancer (CRPC) through genomic analysis.
Abstract No:4562
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4562)
Author(s): Daniel Costin Danila, Aseem Anand, Jianchao Yao, Magdalena Gierszewska, Melissa Kramer,
Stephanie Muller, Martin Fleisher, William R. McCombie, Howard I. Scher; Sidney Kimmel Center for
Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Memorial SloanKettering Cancer Center, New York, NY; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Abstract:
Background: Mutations in the ligand binding domain of androgen receptor (AR) in prostate cancer cells may
alter their sensitivity to treatment with specific antiandrogens. To predict for tumor sensitivity to treatment
with novel AR targeted therapies, we explored the frequency of mutation detection and copy number
alteration in CTC isolated from patients with CRPC enrolled on trials with these targeted therapies. Methods:
We used fluorescence-activated cell sorting (FACS) methodology to enrich EpCAM+, CD45-, DAPI- cells. For
mutation detection and genomic copy number alteration in CTC in low number of cancer cells found in
clinical samples, we optimized next-gen deep sequencing by Illumina. Results: In patients with progressive
CRPC , >10 or >50 EpCAM+ events (EPE) were isolated by FACS in 88% or 58% of patients, in whom 32%
and 10% had unfavorable (>5 cells/7.5 ml) CTC counts using CellSearch. EPE, expressing prostate-specific
mRNAs, provide sufficient high quality DNA for genomic sequencing and copy number analysis. Adequate
coverage was obtained from as few 50 EPE, with a recovery rate of 89% from FACS sorted samples. The
detection threshold of a mutation was established at 1:4 alleles. To further expand genomic profiling in CTC,
we optimized Nimblegen exome mutation detection by deep sequencing on HiSeq PE101. Our initial
analysis established the polymorphism frequency detection thresholds in heterogeneous cell populations,
and confirmed the sequencing coverage. Somatic missense mutations in AR, APC and TP53 found in CTC
but not in paired WBC were confirmed by Sanger sequencing. In parallel, copy number alterations in CTC
are studied. Conclusions: Somatic mutations detected in CTC isolated from patients with CRPC can serve
as predictive markers of tumor sensitivity to targeted therapies. We established standard operating
procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection
thresholds in heterogeneous cell population. Currently we are proceeding to clinical samples to study the
associations between specific molecular alterations in CTC as predictive markers of sensitivity and clinical
outcomes.
A validated whole-blood RNA transcript-based prognostic model that predicts survival in men with
castration-resistant prostate cancer.
Abstract No:4516
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4516)
Author(s): William K. Oh, Philip Kantoff, Howard I. Scher, Jay Magidson, Karl Wassmann, Gwo-Shu Mary
Lee, Leah M. Katz, Sumit Kumar Subudhi, Aseem Anand, Martin Fleisher, Matt D. Galsky, Robert W Ross;
Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine,
New York, NY; Dana-Farber Cancer Institute, Boston, MA; Sidney Kimmel Center for Prostate and Urologic
Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY; Statistical Innovations, Inc., Belmont, MA;
Source MDx, Boulder, CO; Memorial Sloan-Kettering Cancer Center, New York, NY
Abstract:
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.
18F-16β-fluoro-5α-dihydrotestosterone (FDHT) PET as a prognostic biomarker for survival in patients
with metastatic castrate-resistant prostate cancer (mCRPC).
Abstract No:4517
Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4517)
Author(s): Karen A. Autio, Josef J. Fox, Xiaoyu Jia, Glenn Heller, Heiko Schöder, John Humm, Eric C. Haupt,
Coursen Schneider, Howard I. Scher, Steven M. Larson, Michael J. Morris; Memorial Sloan-Kettering Cancer
Center, New York, NY
Abstract:
Background: At present there is no imaging biomarker for patients with mCRPC as the disease primarily
metastasizes to bone, which is difficult to visualize and quantify using standard techniques. We have
conducted clinical trials in which patients with progressive mCRPC are scanned using FDG-PET to examine
glucose metabolism, and FDHT-PET. FDHT is a novel tracer and structural analog of dihydrotestosterone
that binds to the androgen receptor (AR) to demonstrate AR overexpression, a key biologic feature of
mCRPC. We previously reported an association between baseline FDG-PET and overall survival in mCRPC.
We now present the prognostic utility of baseline FDHT-PET. Methods: We prospectively scanned mCRPC
patients with FDG and FDHT-PET prior to a change in therapy as part of imaging clinical trials. PET results
were represented as the hottest lesion (SUVmax), or average of the five hottest lesions (SUVmaxavg). Five
lesions per patient were recorded. If less than 5 lesions were captured, a value of 1 was imputed for the
remaining lesions. Clinical and lab parameters were collected. Univariate analysis was performed on PET,
clinical and lab variables for association with overall survival (OS). Multivariate models of prognostic factors
were constructed. Results: 170 mCRPC patients were imaged with FDG and 116 also had FDHT-PET at
baseline. Median survival was 21.2 months (95%CI: 19.1-24.0). On univariate analysis, FDHTmax,
FDHTmaxavg, FDGmaxavg, PSA, hemoglobin, alkaline phosphatase, and LDH were associated with OS.
FDHTmax and FDHTmaxavg were significantly correlated with one another. In a multivariate model,
FDHTmaxavg and LDH were prognostic of survival. In a separate model assessing FDG, FDGmaxavg and
LDH were also prognostic. Conclusions: FDHT not only allows for a visual assessment of the AR axis in
prostate cancer, but appears to associate with overall survival in mCRPC. Increased AR activity as
measured by FDHT SUVmaxavg held greater prognostic value than PSA or Gleason score. FDHT is also
being evaluated as a clinical response indicator and pharmacodynamic measure with AR directed therapies.