-
EURURO-9157; No. of Pages 9
Prostate Cancer
Ductal Prostate Cancers Demonstrate Poor Outcomes
withConventional Therapies
Weranja Ranasinghe a, Daniel D. Shapiro a, Hyunsoo Hwang a,
Xuemei Wang a,Chad A. Reichard b, Mohamed Elsheshtawi a, Mary F.
Achim a, Tharakeswara Bathala a,Chad Tang a, Ana Aparicio a,
Shi-Ming Tu a, Nora Navone a, Timothy C. Thompson a,Louis Pisters
a, Patricia Troncoso a, John W. Davis a, Brian F. Chapin a,*
a The University of Texas M.D. Anderson Cancer Center, Houston,
TX, USA; bUrology of Indiana, Indianapolis, IN, USA
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X
X
ava i lable at www.sc iencedirect .com
journa l homepage: www.europea nurology.com
Article info
Article history:
Accepted November 10, 2020
Associate Editor:
James Catto
Statistical Editor:
Melissa Assel
Keywords:
Ductal prostate cancerLocalizedOutcomesRadical
prostatectomyRadiotherapyNeoadjuvantAndrogen deprivation
therapy
Abstract
Background: Ductal prostate adenocarcinoma (DAC) is a rare,
aggressive, histologic variantof prostate cancer that is treated
with conventional therapies, similar to high-risk
prostateadenocarcinoma (PAC).Objective: To assess the outcomes of
men undergoing definitive therapy for DAC or high-risk PAC and to
explore the effects of androgen deprivation therapy (ADT) in
improving theoutcomes of DAC.Design, setting, and participants: A
single-center retrospective review of all patients withcT1–4/N0–1
DAC from 2005 to 2018 was performed. Those undergoing radical
prostatec-tomy (RP) or radiotherapy (RTx) for DAC were compared
with cohorts of high-risk PACpatients.Outcome measurements and
statistical analysis: Metastasis-free survival (MFS) and
overallsurvival (OS) rates were analyzed using Kaplan-Meier and Cox
regression models.Results and limitations: A total of 228 men with
DAC were identified; 163 underwent RP,34 underwent RTx, and 31 had
neoadjuvant therapy prior to RP. In this study, 163 DACpatients and
155 PAC patients undergoing RP were compared. Similarly, 34 DAC
patients and74 PAC patients undergoing RTx were compared. DAC
patients undergoing RP or RTx hadworse 5-yr MFS (75% vs 95% and 62%
vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97%and 82%
vs 100%, respectively, p < 0.05) compared with PAC patients. In
the 76 men whoreceived adjuvant/salvage ADT after RP, DAC also had
worse MFS and OS than PAC (p < 0.01).A genomic analysis revealed
that 10/11 (91%) DACs treated with ADT had intrinsic upre-gulation
of androgen-resistant pathways. Further, none of the DAC patients
(0/15) whoreceived only neoadjuvant ADT prior to RP had any
pathologic downgrading. The retro-spective nature was a
limitation.Conclusions: Men undergoing RP or RTx for DAC had worse
outcomes than PAC patients,regardless of the treatment modality.
Upregulation of several intrinsic resistance pathwaysin DAC
rendered ADT less effective. Further evaluation of the underlying
biology of DAC withclinical trials is needed.Patient summary: This
study demonstrated worse outcomes among patients with
ductaladenocarcinoma of the prostate than among high-grade prostate
adenocarcinoma patients,regardless of the treatment modality.
© 2020 Published by Elsevier B.V. on behalf of European
Association of Urology.
. Department of Urology, M.D. Anderson Cancer Center, The
University ofBlvd, Unit 1373, Houston, TX 77030, USA. Tel. +1
(713)794-5590;
* Corresponding authorTexas, 1515 Holcombe Fax: +1
(713)794-4824.
Please cite this article in press as: , et al. Ductal Prostate
Cancers Demonstrate Poor Outcomes with Conventional Therapies.
EurUrol (2020), https://doi.org/10.1016/j.eururo.2020.11.015
https://doi.org/10.1016/j.eururo.2020.11.0150302-2838/© 2020
Published by Elsevier B.V. on behalf of European Association of
Urology.
https://doi.org/10.1016/j.eururo.2020.11.015https://doi.org/10.1016/j.eururo.2020.11.015https://doi.org/10.1016/j.eururo.2020.11.015
-
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X
X2
EURURO-9157; No. of Pages 9
1. Introduction
Ductal adenocarcinoma of the prostate (DAC) is thesecond most
common histologic subtype of prostatecancer (PCa), accounting for
0.1–7% [1,2] cases. AlthoughDACs are usually categorized as
International Society ofUrological Pathology (ISUP) grade group
(GG) �4 disease[3] and display similarly aggressive clinical
behavior [4],they are a unique entity with a poorly understood
biology.Both the diagnosis and the management of DACs
arechallenging, as they often present with locally advanceddisease
and low serum prostate-specific antigen (PSA)levels, and predispose
to early visceral metastasis,especially to the lungs [5–10].
The optimal definitive management of DAC is unknown,as the
current evidence is based exclusively on population-based studies
and small institutional series. Population-based studies,
comprising mainly of men undergoingradical prostatectomy (RP),
demonstrated higher rates ofmetastases and death from DAC than from
high-risk acinaradenocarcinoma of the prostate (PAC) [2,8],
although pureDACs were shown to have similar outcomes to GG 4–5
PACs[9]. Definitive therapy with RP alone frequently fails
tocontrol the high pT3 rates [5,11–13] and 27% pathologicnodal
involvement [12,13] is seen in DAC, resulting inbiochemical
recurrences in up to 70% of patients[4,5,11]. The role of
definitive radiotherapy (RTx) for thetreatment of DAC is also based
solely on a few small casesseries [7,14–18], and none directly
compared its outcomeswith PAC.
Table 1 – Characteristics of patients undergoing RP for DAC
(group 1)
Age, median (25%, 75%) N = 318 PSA, median (25%, 75%) N = 310
Biopsy GG, no. (%) �4 Clinical T stage, no. (%)
1 2 3 4
Clinical N stage, no. (%) 1 Ductal component, no. (%)
Mixed Pure
Prostatectomy specimen GG, no. (%) �4 pT stage, no. (%) T3-T4 pN
stage, no. (%)a N1 Median lymph node count (25%, 75%)a N = 277
Positive margin, no. (%) Biochemical recurrence, no. Local
recurrence, no. Locoregional recurrence, no. Any postop RTx or
systemic therapy, no. Adjuvant or salvage RTx, no. Metastasis, no.
Death, no.
DAC = ductal adenocarcinoma of the prostate; GG = grade group;
PAC = prostate aRTx = radiotherapy.One patient with DAC did not
have pT stage, nodal status, and margin status avaa Seven patients
with DAC did not have a lymph node dissection.b Data were missing
in one patient.
Please cite this article in press as: , et al. Ductal Prostate
Cancers DUrol (2020),
https://doi.org/10.1016/j.eururo.2020.11.015
Adjuvant or salvage androgen deprivation therapy(ADT), with or
without RTx, has been shown to be effectivein treating PAC with
advanced pathology includingpathologic nodal disease or recurrences
after RP, withimproved disease-free survival [19]. Therefore,
adjuvant orsalvage ADT–based therapies are also frequently used
inDAC [10,20], based on the observations that most DACshave
androgen receptor (AR) expression [12,20,21] and thelong-term
responses to ADT demonstrated in small RTxseries [14,16,17] and
metastatic series [16,22]. As up to 93%of patients with DAC present
with � pT3 disease [5,11–13],neoadjuvant use of ADT could also help
downstage thesetumors. However, our recent metastatic series
demon-strated that >85% of men treated with ADT progressedafter
the initial therapy [10], questioning the efficacy ofADT in
DAC.
We aimed to assess the outcomes of men with DACundergoing local
therapy with curative intent comparedwith high-risk PAC patients
undergoing RP or RTx, using thelargest institutional series of DACs
to date. We also exploredthe use of ADT in DAC, in both the
neoadjuvant and the post-RP recurrence setting.
2. Patients and methods
Institutional review board approval was obtained from the MD
AndersonResearch Ethics Committee. A retrospective review of the
records fromall patients referred to our institution from January
2005 throughNovember 2018 and having a histologically verified
diagnosis of DAC wasperformed. Patients who received treatment for
a new diagnosis of DAC
versus high-risk PAC
Ductal (N = 163) Acinar (N = 155) p value
64 (59, 68) 62 (56, 66)
-
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X X
3
EURURO-9157; No. of Pages 9
with cT1–4 and cN0–1/M0 disease (at our institution or presented
aftertreatment at an external institution) were identified through
theelectronic medical records.
DACs were divided into three groups according to treatment:
(1)upfront RP, (2) RTx, and (3) RP after neoadjuvant therapy. Those
whounderwent RP (group 1) or RTx (group 2) were compared
withcontemporary cohorts of high-risk PAC patients undergoing RP or
RTxduring the same period at our institution. High-risk PAC was
defined byPSA > 20 ng/ml or GG 4–5 or clinical stage � T3.
Separate comparisonswere performed to compare between the outcomes
of patientsundergoing RP compared with those of patients undergoing
RTx forDAC (group 1 vs 2) and the effects of neoadjuvant therapy
among DACpatients undergoing RP (group 1 vs 3).
Demographic and cancer-related data, including age, date of
PCadiagnosis, PSA values, clinical T stage, GG, composition of DAC
(pure ormixed), type of treatment, progression, dates of
metastases, and survivaldata, were collected. Date of diagnosis was
defined as the date of prostatebiopsy. Biochemical recurrence (BCR)
following RP was defined as serumPSA � 0.2 ng/ml followed by a
second confirmatory level. TNM stagingwas based on American Joint
Committee on Cancer (AJCC) criteria.Metastases were identified on
computed tomography, or bone scansperformed for staging in all
patients; some patients also had magneticresonance imaging or
positron emission tomography–based imaging orbiopsy of the lesions.
Local recurrence was defined as recurrences at theanastomotic site
and locoregional recurrences as pelvic recurrenceswithout distant
metastases diagnosed on imaging or biopsy.
All pathologic specimens were reviewed by dedicated
genitourinarypathologists at our institution as part of their
clinical workup. DAC wasidentified either on biopsy or on RP, and
categorized as pure DAC (whichincluded tumors that had DAC
predominantly) or as mixed DAC(associated with acinar
adenocarcinoma), in order to minimize the biasassociated with the
percentage of the DAC component.
2.1. Genomic data
Genomic data from all patients in this series who had somatic
DNAsequencing performed as part of routine clinical care were
included. Agenomic analysis was performed by the MD Anderson
MolecularDiagnostics Laboratory using polymerase chain
reaction–based next-generation sequencing of DNA based on three
targeted gene panels:Mutational Analysis Panel (50 genes), Solid
Tumor Genomic Analysis(STGA) version 1 (134 genes), and STGA 2018
(146 genes). Additional dataon the gene panels are provided in
Supplementary Table 1.
2.2. Statistical analysis
Patient characteristics are summarized using frequency (%)
forcategorical variables and median with interquartile range for
continuousvariables. The probabilities of overall survival (OS) and
metastasis-freesurvival (MFS) were estimated using the Kaplan-Meier
method [23]. The
Table 2 – Multivariable Cox regression analysis for MFS or OS in
men uvariables of histology, age, PSA, biopsy GG, cT stage, pT
stage, pN stage
HR (95% CI for H
Histology DAC vs PAC 3.12 (1.66–5.86) Prostatectomy specimen GG
�4 vs
-
Table 3 – MFS and OS in men undergoing RP for DAC (group 1) or
RTx (group 2) versus high-risk PAC patients undergoing RP or
RTx
DAC DAC PAC PAC
No. of patients at risk % (95% CI) No. of patients at risk %
(95% CI)
RP3-yr MFS 155 83 (77–90) 163 96 (92–99)5-yr MFS 155 75 (68–84)
163 95 (91–99)3-yr OS 155 97 (94–100) 163 99 (98–100)5-yr OS 155 88
(82-95) 163 97 (95–100)RTx3-yr MFS 34 84 (72–98) 74 100
(100–100)5-yr MFS 34 62 (46–83) 74 93 (88–99)3-yr OS 34 93 (85–100)
74 100 (100–100)5-yr OS 34 82 (69–98) 74 100 (100–100)
CI = confidence interval; DAC = ductal adenocarcinoma of the
prostate; MFS = metastasis-free survival; OS = overall survival;
PAC = prostate adenocarcinoma;RP = radical prostatectomy; RTx =
radiotherapy.
Fig. 1 – (A) Kaplan-Meier curve for MFS in men undergoing RP for
DAC (group 1) or high-risk PAC (p < 0.001; truncated). The
median follow-up was56.5 mo (IQR 32) for PAC and 44 mo (IQR 54.7)
for DAC in men without events. (B) Kaplan-Meier curve for OS in men
undergoing RP for DAC (group 1)or high-risk PAC (p = 0.04;
truncated). The median follow-up was 54.7 mo (IQR 33) for PAC and
48 mo (IQR 58.2) for DAC in men without events. (C)Kaplan-Meier
curve for MFS in men undergoing RTx for DAC (group 2) or high-risk
PAC (p < 0.001; truncated). The median follow-up was 73 mo
(IQR42) for PAC and 74 mo (IQR 76.5) for DAC in men without events.
(D) Kaplan-Meier curve for OS in men undergoing RTx for DAC (group
2) or high-riskPAC (p = 0.004; truncated). The median follow-up was
75.5 mo (IQR 41.7) for PAC and 74 mo (IQR 38.4) for DAC in men
without events. DAC = ductaladenocarcinoma of the prostate; IQR =
interquartile range; MFS = metastasis-free survival; OS = overall
survival; PAC = prostate adenocarcinoma; RP =radical prostatectomy;
RTx = radiotherapy.
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X
X4
EURURO-9157; No. of Pages 9
Please cite this article in press as: , et al. Ductal Prostate
Cancers Demonstrate Poor Outcomes with Conventional Therapies.
EurUrol (2020), https://doi.org/10.1016/j.eururo.2020.11.015
https://doi.org/10.1016/j.eururo.2020.11.015
-
Fig. 2 – (A) Kaplan-Meier curve for MFS in men receiving
adjuvant or salvage ADT after RP for DAC (group 1) or high-risk PAC
(truncated). (B) Kaplan-Meier curve for OS in men receiving
adjuvant or salvage ADT after RP for DAC (group 1) or high-risk PAC
(truncated). ADT = androgen deprivationtherapy; DAC = ductal
adenocarcinoma of the prostate; MFS = metastasis-free survival; OS
= overall survival; PAC = prostate adenocarcinoma; RP =
radicalprostatectomy.
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X X
5
EURURO-9157; No. of Pages 9
Please cite this article in press as: , et al. Ductal Prostate
Cancers Demonstrate Poor Outcomes with Conventional Therapies.
EurUrol (2020), https://doi.org/10.1016/j.eururo.2020.11.015
https://doi.org/10.1016/j.eururo.2020.11.015
-
Fig. 3 – Genomic analysis of targeted genes in 11 patients who
underwent local therapy for DAC. ADT = androgen deprivation
therapy; DAC = ductaladenocarcinoma of the prostate; DDR = DNA
damage repair; RP = radical prostatectomy; RTx = radiotherapy.
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X
X6
EURURO-9157; No. of Pages 9
88% versus 97% (p = 0.03; Table 3 and Fig. 1B), respectively.On
a subgroup analysis of pT3/4 and pathologic GG 4–5 atRP
(Supplementary Fig. 1A and 1B) and a weighted Coxregression
analysis (Supplementary Table 2), DACs still hadworse MFS and OS
than PACs. Pure DACs had worse MFSthan mixed DACs and PACs
(Supplementary Fig. 1C and 1D).
3.2. Outcomes of men undergoing RTx
In the RTx cohort, 34 men (14.9%) with DAC (group 2)
werecompared with 74 men with high-risk PAC undergoing RTx.The
baseline characteristics are seen in SupplementaryTable 3. Complete
radiation dose details were available onlyfor 25 DAC patients. The
mean radiation doses were 76.1 Gyin the DAC and 76.3 Gy in the PAC
(p = 0.49) group, and themean ADT use was 17.8 and 19.8 mo (p =
0.25), respectively.Of men with DAC, 28% received brachytherapy
boostscompared with 35% of men with PAC (p = 0.63).
In men undergoing RTx, DAC was an independent riskfactor for MFS
(HR 3.66, 95% CI 1.54–8.67, p < 0.001) and OS(HR 3.15, 95% CI
1.09–9.14, p = 0.03) on a multivariable
Please cite this article in press as: , et al. Ductal Prostate
Cancers DUrol (2020),
https://doi.org/10.1016/j.eururo.2020.11.015
analysis when considering variables of histology, age,
PSA,biopsy GG, cT stage, and CN stage (Supplementary Table 4).The
duration of ADT use with RTx was not associated withMFS or OS.
On a Kaplan-Meier analysis, patients with DAC hadworse MFS and
OS at 3 and 5 yr than patients with PACundergoing definitive RTx
(Table 3, and Fig. 1C and 1D).
On comparison of DAC patients who underwent RP(group 1) with
those who had RTx (group 2; SupplementaryTable 5), there were no
statistically significant differences inMFS or OS between men with
DAC undergoing RP and thoseundergoing RTx (Supplementary Table 6,
and Supplemen-tary Fig. 2A and 2B).
3.3. Treatment for recurrence after local therapy
Although, there were similar rates of pT3 disease, pN1,
andpositive margins between DAC and PAC patients undergoingRP, DACs
had higher rates of BCR (49% vs 31.1%, p < 0.001)and
locoregional recurrences (6.6% vs 1.9%, p = 0.01; Table 1).
Compared with men with PAC, a higher proportion of
emonstrate Poor Outcomes with Conventional Therapies. Eur
https://doi.org/10.1016/j.eururo.2020.11.015
-
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X X
7
EURURO-9157; No. of Pages 9
men with DAC undergoing RP received adjuvant or salvageRTx or
ADT (59.5% vs 40.9%, p = 0.002); yet, worse MFS wasseen in the DAC
group after adjuvant or salvage RTxfollowing RP (p = 0.038;
Supplementary Fig. 3). Further,among men who received only ADT as
post-RP adjuvant orsalvage therapy, those with DAC had worse MFS
and OS thanmen with PAC (both p < 0.01; Fig. 2A and 2B).
To assess the mechanisms responsible for poor responsesto ADT
seen in men with DAC,11 men who had targeted genesequencing as part
of their clinical workup were identified(Fig. 3). No two men had
similar gene profiles, but ten out of11 (90.1%) who received ADT
had alterations in one or moregenes upregulating DNA damage repair
(DDR), PI3K/AKT,WNT/b catenin, or TP53 pathways associated with
andro-gen resistance [24]. Eight out of 11 (82%) men who
hadadjuvant/salvage ADT alone or with RTx progressed withlocal
recurrence or developed metastatic disease. Of the twopatients who
did not progress after ADT, one (patient 1) hada single mutation in
the HRAS gene, which is not associatedwith AR resistance and had no
recurrence at 18.8 mo withsalvage ADT after RP. The other patient
(patient 2) receivedneoadjuvant ADT in combination with docetaxel
prior to RP,which was continued after surgery, and had no
recurrenceat 20.3-mo follow-up since initiating therapy,
despitemutations in the PI3K/AKT and TP53 pathways.
3.4. Patients with DAC receiving neoadjuvant therapy prior
to
RP
Thirty-one men with DAC received neoadjuvant therapyprior to RP
as part of a clinical trial or at physician discretion(group 3;
Supplementary Table 7). None of the 15 men withDAC who received
single therapy ADT had any pathologicdownstaging. One patient who
received docetaxel and ADTachieved pathologic complete response
(pCR), and twopatients who had abiraterone with ADT achieved 1),
demonstrating that,on average, DAC patients had worse MFS than PAC
patients.Similar findings were detected for OS. A number of
studieshave demonstrated worse outcomes with DAC
[4,6,8,11],including a propensity-matched analysis of 253 men
withDAC undergoing RP in the Surveillance, Epidemiology, andEnd
Results (SEER) database, which reported worse 10-yrcancer-specific
mortality compared with men with PAC(92% vs 95.4%) [2]. In
contrast, another study using theNational Cancer Database (NCDB)
demonstrated similar OSbetween pure DAC and GG 4–5 PAC patients
(91.7%) [9]. Thedefinition of pure DAC or percentage of DAC,
interobservervariability, and the lack of data on adjuvant
treatment inpopulation-based studies could account for these
differ-ences.
To our knowledge, the present study is the first
directcomparison of RTx outcomes of DAC and PAC. Similar to themen
undergoing RP, those undergoing RTx for DAC also hadworse MFS and
OS than patients undergoing RTx for PAC.Further, RTx had similar
outcomes to RP in treating patientswith DAC. Although one study
reported worse rates of BCRand OS with RTx than with RP in a series
of 14 men with DAC[18], several other small series have shown the
efficacy ofRTx in DAC with long-term outcomes [14–18]. While ourRTx
series is the largest to date, the small sample size makesa
meaningful comparison between RP and RTx difficult.
Despite similar grade, stage, pathologic nodal status,
andpositive margin rates between DAC and PAC at RP, DACs hadhigher
rates of biochemical failure and 59.5% of DACpatients received
adjuvant or salvage therapies. AlthoughADT was initially believed
to be ineffective against DACs dueto possible endometrial origins
[25], recent studies dem-onstrated AR activity [20,21] and
long-term responses toADT [14,16,17,22], endorsing its use in DAC.
In contrast, ourstudy demonstrates that ADT is less effective in
treatingrecurrences of DAC than of PAC, with 10/11 (90.1%)
mentreated with ADT having upregulation of one or moreresistance
pathways on genomic analysis. DACs have agenomic makeup similar to
those with advanced PCa, withupregulation of a number of pathways
such as DDR, PI3K-Akt, Wnt/b-Catenin, TP53, and FOXA1 [21,26].
Despitesimilar clonal origins to PAC and the presence of
ARsignaling at the genomic, transcriptomic, and protein
levels[12,21,27], DACs have upregulation of these
pathwaysdeveloping early resistance to AR [24]. Although no twoDACs
have similar genomic profiles, alterations in differentgene
combinations cause activation of one or more of thesepathways
[21,26], making a single-gene–targeted therapeu-tic approach almost
impossible. Thus, the role of noveltherapies targeting a
combination of gene or pathways, suchas poly ADP ribose polymerase
(PARP) inhibitors orimmunotherapy for DACs, should be investigated,
as 49%of patients with DACs are enriched for DDR gene
alterations[26].
Similar to the postsurgical setting, DACs also had nopathologic
downstaging with only ADT as neoadjuvanttherapy. In keeping with
this, another study identified that
emonstrate Poor Outcomes with Conventional Therapies. Eur
https://doi.org/10.1016/j.eururo.2020.11.015
-
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X
X8
EURURO-9157; No. of Pages 9
DAC was an independent risk factor for developing drugresistance
to neoadjuvant ADT prior to RP [28]. Yet, in ourstudy, two patients
who received maximal androgenblockade with the ADT/abiraterone
combination achievedMRD, one achieved pCR with ADT/docetaxel, and
nonedeveloped metastases. Neoadjuvant maximal androgenblockade in
PAC has marginal pCR [29] and survival benefitswith chemohormonal
therapies [30] in men undergoing RP,and generally excludes DAC;
further evaluation of thesetherapies in RP and definitive RTx
therapy in DAC iswarranted.
While our study had a relatively large sample size andin-depth
data mining, the main limitations are itsretrospective nature;
small sample size owing to the rarityof the disease, which could
have affected the likelihoodand the effect size leading to a
possible bias; and the lack ofgeneralizability of the outcomes from
a high-volumeacademic center. Some patients who were referred toour
institution, after treatment elsewhere, had missingclinical data,
which may have influenced some of ourresults. Furthermore, most of
these patients did not havemolecular profiling, and for the 11
patients who did, onlytargeted sequencing data were available.
Therefore, ourstudy may not have given complete insight into
thegenomic makeup of DACs. Additionally, as our aim was toassess
the outcomes of men with any DAC component andreduce subjectivity,
we did not assess the percentage ofDAC and may have biased our
results.
5. Conclusions
In conclusion, DAC had worse outcomes than PAC in menundergoing
RP or RTx with curative intent. The majority ofpatients with DAC
failed ADT single therapy in both theadjuvant/salvage and the
neoadjuvant setting due to theupregulation of a number of
resistance pathways, renderingtherapy less effective. Further
evaluation of the underlyingbiology of DAC and developing clinical
trials leveraging thisbiology to develop multimodal or
pathway-targeted thera-pies are needed.
Author contributions: Brian F. Chapin had full access to all the
data in thestudy and takes responsibility for the integrity of the
data and theaccuracy of the data analysis.
Study concept and design: Ranasinghe, Chapin.Acquisition of
data: Elsheshtawi, Achim, Ranasinghe.Analysis and interpretation of
data: Ranasinghe, Hwang, Wang, Chapin.Drafting of the manuscript:
Ranasinghe, Shapiro.Critical revision of the manuscript for
important intellectual content:Reichard, Bathala, Tang, Aparicio,
Tu, Navone, Thompson, Pisters,Troncoso, Davis, Chapin.Statistical
analysis: Hwang, Wang, Ranasinghe, Shapiro.Obtaining funding:
None.Administrative, technical, or material support:
None.Supervision: Bathala, Tang, Aparicio, Tu, Navone, Thompson,
Pisters,Troncoso, Davis, Chapin.Other: None.
Please cite this article in press as: , et al. Ductal Prostate
Cancers DUrol (2020),
https://doi.org/10.1016/j.eururo.2020.11.015
Financial disclosures: Brian F. Chapin certifies that all
conflicts ofinterest, including specific financial interests and
relationships andaffiliations relevant to the subject matter or
materials discussed in themanuscript (eg, employment/affiliation,
grants or funding, consultan-cies, honoraria, stock ownership or
options, expert testimony, royalties,or patents filed, received, or
pending), are the following: None.
Funding/Support and role of the sponsor: Weranja Ranasinghe was
arecipient of the American Urological Association (AUA) / Urology
CareFoundation Research Scholar Award.
Appendix A. Supplementary data
Supplementary material related to this article can befound, in
the online version, at
doi:https://doi.org/10.1016/j.eururo.2020.11.015.
References
[1] Humphrey PA. Histological variants of prostatic carcinoma
and theirsignificance. Histopathology 2012;60:59–74.
[2] Knipper S, Preisser F, Mazzone E, et al. Contemporary
comparison ofclinicopathologic characteristics and survival
outcomes of prostateductal carcinoma and acinar adenocarcinoma: a
population-basedstudy. Clin Genitourin Cancer 2019;17, 231–7
e2.
[3] Epstein JI. An update of the Gleason grading system. J
Urol2010;183:433–40.
[4] Kim A, Kwon T, You D, et al. Clinicopathological features of
prostateductal carcinoma: matching analysis and comparison with
prostateacinar carcinoma. J Korean Med Sci 2015;30:385–9.
[5] Seipel AH, Wiklund F, Wiklund NP, Egevad L.
Histopathologicalfeatures of ductal adenocarcinoma of the prostate
in 1,051 radicalprostatectomy specimens. Virchows Arch
2013;462:429–36.
[6] Brinker DA, Potter SR, Epstein JI. Ductal adenocarcinoma of
theprostate diagnosed on needle biopsy: correlation with clinical
andradical prostatectomy findings and progression. Am J Surg
Pathol1999;23:1471–9.
[7] Tu SM, Lopez A, Leibovici D, et al. Ductal adenocarcinoma of
theprostate: clinical features and implications after local
therapy.Cancer 2009;115:2872–80.
[8] Morgan TM, Welty CJ, Vakar-Lopez F, Lin DW, Wright JL.
Ductaladenocarcinoma of the prostate: increased mortality risk and
de-creased serum prostate specific antigen. J Urol
2010;184:2303–7.
[9] Packiam VT, Patel SG, Pariser JJ, et al. Contemporary
population-based comparison of localized ductal adenocarcinoma and
high-risk acinar adenocarcinoma of the prostate. Urology
2015;86:777–82.
[10] Ranasinghe WKB, Brooks NA, Elsheshtawi M, et al. Patterns
ofmetastases of prostatic ductal adenocarcinoma.
Cancer2020;126:3667–73.
[11] Jang WS, Shin SJ, Yoon CY, et al. Prognostic significance
of theproportion of ductal component in ductal adenocarcinoma of
theprostate. J Urol 2017;197:1048–53.
[12] Jeong SU, Kekatpure AK, Park JM, et al. Diverse
immunoprofile ofductal adenocarcinoma of the prostate with an
emphasis on theprognostic factors. J Pathol Transl Med
2017;51:471–81.
[13] Christensen WN, Steinberg G, Walsh PC, Epstein JI.
Prostatic ductadenocarcinoma. Findings at radical prostatectomy.
Cancer1991;67:2118–24.
[14] Eade TN, Al-Saleem T, Horwitz EM, Buyyounouski MK, Chen
DY,Pollack A. Role of radiotherapy in ductal (endometrioid)
carcinomaof the prostate. Cancer 2007;109:2011–5.
emonstrate Poor Outcomes with Conventional Therapies. Eur
https://doi.org/10.1016/j.eururo.2020.11.015https://doi.org/10.1016/j.eururo.2020.11.015http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0005http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0005http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0010http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0010http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0010http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0010http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0015http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0015http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0020http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0020http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0020http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0025http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0025http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0025http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0030http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0030http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0030http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0030http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0035http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0035http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0035http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0040http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0040http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0040http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0045http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0045http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0045http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0045http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0050http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0050http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0050http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0055http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0055http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0055http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0060http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0060http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0060http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0065http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0065http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0065http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0070http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0070http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0070https://doi.org/10.1016/j.eururo.2020.11.015
-
E U R O P E A N U R O L O G Y X X X ( 2 0 2 0 ) X X X – X X X
9
EURURO-9157; No. of Pages 9
[15] Bergamin S, Eade T, Kneebone A, et al. Ductal carcinoma of
theprostate: an uncommon entity with atypical behaviour. Clin
Oncol(R Coll Radiol) 2019;31:108–14.
[16] Orihuela E, Green JM. Ductal prostate cancer: contemporary
man-agement and outcomes. Urol Oncol 2008;26:368–71.
[17] Nakamura K, Terada N, Kobayashi T, et al. [Clinical
characteristics ofprostate ductal adenocarcinoma in Kyoto
University Hospital].Hinyokika Kiyo 2015;61:487–91.
[18] Igdem S, Spiegel DY, Efstathiou J, et al. Prostatic duct
adenocarci-noma: clinical characteristics, treatment options, and
outcomes—aRare Cancer Network study. Onkologie 2010;33:169–73.
[19] Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD.
Neo-adjuvant and adjuvant hormone therapy for localised and locally
ad-vanced prostate cancer. Cochrane Database Syst Rev
2006;4:CD006019.
[20] Vinceneux A, Bruyere F, Haillot O, et al. Ductal
adenocarcinoma of theprostate: clinical and biological profiles.
Prostate 2017;77:1242–50.
[21] Gillard M, Lack J, Pontier A, et al. Integrative genomic
analysis ofcoincident cancer foci implicates CTNNB1 and PTEN
alterations inductal prostate cancer. Eur Urol Focus
2019;5:433–42.
[22] Millar EK, Sharma NK, Lessells AM. Ductal (endometrioid)
adeno-carcinoma of the prostate: a clinicopathological study of 16
cases.Histopathology 1996;29:11–9.
[23] Schemper M, Smith TL. A note on quantifying follow-up in
studiesof failure time. Control Clin Trials 1996;17:343–6.
Please cite this article in press as: , et al. Ductal Prostate
Cancers DUrol (2020),
https://doi.org/10.1016/j.eururo.2020.11.015
[24] Huang Y, Jiang X, Liang X, Jiang G. Molecular and cellular
mechanismsof castration resistant prostate cancer. Oncol Lett
2018;15:6063–76.
[25] Melicow MM, Tannenbaum M. Endometrial carcinoma of
uterusmasculinus (prostatic utricle). Report of 6 cases. J
Urol1971;106:892–902.
[26] Schweizer MT, Antonarakis ES, Bismar TA, et al. Genomic
characteri-zation of prostatic ductal adenocarcinoma identifies a
high prevalenceof DNA repair gene mutations. JCO Precis Oncol
2019;3:PO.18.00327.
[27] Seipel AH, Samaratunga H, Delahunt B, Wiklund P, Clements
M,Egevad L. Immunohistochemistry of ductal adenocarcinoma of
theprostate and adenocarcinomas of non-prostatic origin: a
compara-tive study. APMIS 2016;124:263–70.
[28] Wang X, Qi M, Zhang J, et al. Differential response to
neoadjuvanthormonal therapy in prostate cancer: predictive
morphologicalparameters and molecular markers. Prostate
2019;79:709–19.
[29] McKay RR, Ye H, Xie W, et al. Evaluation of intense
androgendeprivation before prostatectomy: a randomized phase II
trial ofenzalutamide and leuprolide with or without abiraterone. J
ClinOncol 2019;37:923–31.
[30] Eastham JHS, Monk JP, Beltran H, et al. LBA-12:
Late-breakingabstract: CALGB 90203 (Alliance): radical
prostatectomy with orwithout neoadjuvant chemohormonal therapy in
men with clini-cally localized, high risk prostate cancer. Chicago:
American Urolo-gy Association Annual Meeting; 2019.
emonstrate Poor Outcomes with Conventional Therapies. Eur
http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0075http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0075http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0075http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0080http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0080http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0085http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0085http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0085http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0090http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0090http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0090http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0095http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0095http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0095http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0100http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0100http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0105http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0105http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0105http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0110http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0110http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0110http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0115http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0115http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0120http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0120http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0125http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0125http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0125http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0130http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0130http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0130http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0135http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0135http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0135http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0135http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0140http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0140http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0140http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0145http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0145http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0145http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0145http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0150http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0150http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0150http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0150http://refhub.elsevier.com/S0302-2838(20)30879-4/sbref0150https://doi.org/10.1016/j.eururo.2020.11.015
Ductal Prostate Cancers Demonstrate Poor Outcomes with
Conventional Therapies1 Introduction2 Patients and methods2.1
Genomic data2.2 Statistical analysis
3 Results3.1 Outcomes of men undergoing RP3.2 Outcomes of men
undergoing RTx3.3 Treatment for recurrence after local therapy3.4
Patients with DAC receiving neoadjuvant therapy prior to RP
4 Discussion5 ConclusionsAppendix A Supplementary
dataReferences