Ductal Prostate Cancers Demonstrate Poor Outcomes with … · Ductal prostate cancer Localized...

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

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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

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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)

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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.




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.





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.



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


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




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





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.


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.

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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

Ductal Prostate Cancers Demonstrate Poor Outcomes with … · Ductal prostate cancer Localized...

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