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The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer

Authors:
  • University Hospitals Parma Medical Center

Abstract and Figures

Background: Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. Patients and methods: Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. Results: Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. Conclusion: Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol.
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Transdermal*oestrogen*in*prostate*cancer*
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The$use$of$Transdermal$Oestrogen$in$Castrate-
resistant,$Steroid-refractory$Prostate$Cancer$
Smith$K.1,$Galazi$M1,$Openshaw$M.$R.2*,$Wilson$P.1,$Sarker$S.$J.3,$O’Brein$N.1,$Alifrangis$
C1,$Stebbing$J.2$$and$Shamash$J1$
1Barts$Cancer$Institute,$Saint$Bartholomew’s$Hospital,$London,$UK$
2$ Department$ of$ Medical$ Oncology,$ Charing$ Cross$ Hospital,$ Imperial$ College$ NHS$
Trust,$London,$UK$
3Centre$ for$ Experimental$ Cancer$ Medicine,$ Queen$ Mary$ $ University$ of$ London,$
London,$UK$
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Corresponding$author:$
$
Dr$Jonathan$Shamash$
jonathan.shamash@bartshealth.nhs.uk$
Department$of$Medical$Oncology,$St$Bartholomew’s$Hospital,$West$Smithfield,$EC1A$
7BE,$UK$
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CTA$number$14620/0013/001$
Protocol$number$PR-2004-04$issued$by$MHRA$
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Key$ Words:$ Castrate$ resistant$ prostate$ cancer,$ transdermal$ oestradiol,$
diethylstilbestrol,$PSA$
*Manuscript
Click here to download Manuscript: oestradiol paper_with revisions.pdf
Transdermal*oestrogen*in*prostate*cancer*
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Microabstract$
We$ aimed$ to$ investigate$ the$ role$ and$ safety$ of$ transdermal$ oestrogen$ therapy$ in$
castrate$ resistant$ prostate$ cancer.$Within$ this$ dose$ escalation$ study$we$ observed$
reduction$ in$ PSA$ levels$ at$ all$ doses$ used.$ In$ addition,$no$ venous$ thromboembolic$
events$ were$ detected$ making$ the$ use$ of$ transdermal$ oestradiol$ a$ safe$ treatment$
option$for$a$subgroup$of$patients$with$castration-resistant$prostate$cancer.$
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Abstract$
Background:$ Androgen-deprivation$ therapy$ is$the$ mainstay$ of$ treatment$for$
metastatic$prostate$ cancer.$Corticosteroids$and$oestrogens$are$also$useful$agents$in$
castrate$ resistant$ prostate$cancer.$ However,$ oral$ oestrogens$ are$ associated$ with$
thromboembolic$events,$which$limits$their$use$and$transdermal$oestrogens$may$offer$
a$ safer$ alternative.$This$ study$ was$ carried$ out$ to$determine$ the$ safety$ and$
effectiveness$of$transdermal$oestrogens$in$castrate$resistant$prostate$cancer.$
Patients$and$ Methods:$41$ patients$ with$ castration$ and$ steroid-resistant$ prostate$
cancer$ were$ eligible$ for$ this$ dose-escalation$ study$ of$ transdermal$ oestradiol.$ A$
starting$ dose$ of$ 50mcg/24$ hours$ was$ applied$ and$ increased$ if$ PSA$ rose$ >5ng/ml$ in$
steps$ to$ 300mcg/24hours.$ The$ primary$ endpoint$ was$ PSA$ response$ and$ secondary$
outcomes$ included$ incidence$ of$ thromboembolic$ events$ and$ progression$ free$
survival.$Patients$who$progressed$were$offered$diethylstilbestrol.$
Results:$5/40$ patients$ (13%)$ had$ >50%$ PSA$ reduction$ for$ at$ least$ 1$ month$ at$ any$
transdermal$oestradiol$dose.$No$venous-thromboembolic$events$were$observed$and$
responses$ plateaued$at$ 200mcg/24hours.$ A$ correlation$ between$ PSA$ response$ and$
rising$ sex$ hormone$ binding$ globulin$was$ seen.$ 50%$ of$ patients$subsequently$
responded$to$low$dose$diethylstilbestrol.$
Conclusion:$Transdermal$oestradiol$appears$to$be$a$low$toxicity$treatment$option$to$
control$ CRPC$after$ failure$ of$ steroid$ therapy.$ Modulation$ of$ sex$ hormone$ binding$
Transdermal*oestrogen*in*prostate*cancer*
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globulin$by$transdermal$oestradiol$may$be$one$mechanism$of$action$of$oestrogens$on$
castrate$resistant$prostate$cancer.$Oral$oestrogens$ remain$effective$after$the$use$of$
transdermal$oestradiol.$$
$ $
Transdermal*oestrogen*in*prostate*cancer*
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Abbreviations:$$
TDE$=$Transdermal$oestrogen$
CRPC$=$castrate-resistant$prostate$cancer$
PSA$=$prostate$specific$antigen$
ADT$=$androgen$deprivation$therapy$
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Transdermal*oestrogen*in*prostate*cancer*
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Introduction:$
Prostate$ cancer$ is$ the$ commonest$ cancer$ in$ men$and$ the$ second$ most$ common$
cause$of$cancer-related$death$in$men$in$the$ UK$ (1).$The$disease$exhibits$remarkable$
heterogeneity$in$clinical$behaviour$and$outcome$ranging$from$years$of$indolence$to$
lethal$disease$despite$similar$histological$features$(2).$$Androgen$deprivation$therapy$
(ADT)$is$the$standard$of$care$for$metastatic$prostate$cancer$and$it$also$has$a$role$in$
the$ neoadjuvant$ and$ adjuvant$ settings.$ Initial$ response$ rates$ to$ ADT$ exceed$ 80%,$
however$these$are$transient$and$patients$invariably$progress$to$the$more$aggressive$
phenotype$of$ the$ disease$ termed$ castration-resistant$ prostate$ cancer$ or$ CRPC$ (3).$
ADT$is$ most$ often$ achieved$ by$ administration$ of$ gonadotropin-releasing$ hormone$
(GnRH)$ analogues$(4).$ Their$ use$ is$associated$ with$ numerous$ long-term$ toxicities$
including$ hot$ flushes,$ gynaecomastia,$ increased$ cardiovascular$events$ and$ reduced$
bone$mineral$density$(4-6).$
Even$ at$ the$ time$ of$ development$ of$ resistance$ to$ ADT,$ research$ has$ demonstrated$
that$androgen$receptor$(AR)$signaling$remains$crucial$for$the$progression$of$CRPC.$As$
a$ result,$ potent$ second$ generation$ anti-androgen$ drugs$ have$ been$ developed$ that$
target$the$AR$pathway.$More$specifically,$abiraterone$acetate$and$enzalutamide$have$
both$ been$ approved$ for$ use$ in$ the$ pre-$ and$ post-chemotherapy$ settings$ following$
improvements$in$ OS$in$ men$ with$ CRPC$ (7-10).$ Despite$ their$impressive$ responses,$
however,$these$novel$treatments$are$associated$with$ numerous$ toxicities$especially$
Transdermal*oestrogen*in*prostate*cancer*
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within$the$ elderly$prostate$ cancer$ patient$ population$ who$might$not$tolerate$ these$
treatments$well.$Toxicities$include$fatigue,$oedema,$hypertension$and$diarrhea.$As$a$
result,$ there$ has$ been$ a$ renewed$ interest$ in$ oestrogen$therapy,$ particularly$ for$
patients$who$are$less$fit$with$relatively$low$volume$disease$and$where$chemotherapy$
and$ second$ generation$ anti-androgens$ may$ result$ in$ significant$ toxicity$ with$
associated$effects$on$quality$of$life.$
$
Oral$oestrogen,$ in$ particular$ Diethylstilbestrol$ (DES),$ is$ an$alternative$ agent$used$ to$
induce$medical$castration$(11),$and$prior$to$the$development$of$GnRH$analogues$was$
the$ mainstay$ of$ treatment.$ $ Oestrogen$ decreases$ testosterone$ concentration$ in$
serum$by$suppressing$LH$ production$ from$the$pituitary$via$negative$feedback.$Their$
use$ however,$ was$ abandoned$ due$ to$ their$ association$ with$ venous$
thromboembolism$ (VTE)$ and$ cardiovascular$ toxicity$ (12,$ 13).$ This$ VTE$ risk$ is$
attributed$to$the$effects$of$first$pass$hepatic$metabolism$of$oestrogen$on$coagulation$
proteins$ and$ lipids$ (14).$ Since$ the$ development$ of$ ADT$ using$ GnRH$ analogues,$ the$
main$ use$ of$ DES$ has$ been$ as$ second,$ third$ or$ consecutive$ line$ hormonal$
manipulation.$$$
$
Parenteral$ oestrogens$ have$ been$ shown$ to$ avoid$ first-pass$ metabolism$ in$ the$ liver$
and$ are$ therefore$ not$ expected$ to$ be$ associated$ with$ the$ same$ frequency$ of$
Transdermal*oestrogen*in*prostate*cancer*
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thromboembolic$ events$ as$oral$ oestrogens$ (14).$ Langley$ et$ al$conducted$ a$
randomized$trial$ of$ GnRH$ analogues$ versus$ transdermal$ oestrogen$ (TDE)$ in$
treatment$naïve$locally$advanced$and$metastatic$prostate$cancer$(15).$ TDE$achieved$
equivalent$levels$ of$ castrate$ testosterone$ concentrations$and$ had$similar$ frequency$
of$VTE$complications.$Rates$of$cardiovascular$toxic$effects$were$similar$with$the$two$
treatments$and$were$lower$than$those$seen$with$oral$oestrogen.$As$TDE$may$achieve$
castrate$ levels$ of$ testosterone$ with$ fewer$ cardiovascular$ and$ vascular$thrombotic$
events$it$has$also$been$trialed$in$CRPC.$Furthermore,$PSA$response$rates$have$been$
seen$in$Phase$II$studies$using$TDE$with$no$increases$in$ VTE$or$cardiovascular$events$
(16).$ Response$ rates$ have$ also$ been$ demonstrated$ in$ chemo-refractory$ prostate$
cancer$(17).$However,$the$long-term$efficacy$of$TDE$versus$DES$is$not$known.$$
$
This$dose-escalation$study$of$TDE$was$therefore$designed$to$assess$the$effectiveness$
of$ TDE$ in$ castrate$ resistant$and$ steroid$ refractory$ advanced$ prostate$ cancer$in$
patients$ who$ had$ declined$ or$ felt$ to$ be$ inappropriate$ for$ chemotherapy.$ Patients$
who$came$ off$ study$ were$ offered$ DES$ to$ establish$ if$ there$ is$any$ cross-resistance$
between$TDE$and$DES.$$PSA$was$used$as$a$marker$for$response.$
$
$ $
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Materials$and$Methods$
Patients$
Eligibility$ criteria$ included$ patients$ with$ confirmed$ locally$ advanced$ or$ metastatic$
prostate$ cancer$ with$progression$ of$ disease$ to$ both$ GnRH$analogues$ and$ steroid$
therapy$equivalent$ to$dexamethasone$ 2mg$once$ a$day,$ prednisolone$15mg$per$ day$
or$20mg$hydrocortisone$per$day.$Patients$were$required$to$be$biochemically$castrate$
at$baseline$(serum$testosterone$<2nmol/l).$$
Men$ aged$ ³$18$ years$ with$ an$ Eastern$ Co-operative$ Oncology$ Group$(ECOG)$
performance$ status$ ³$3$ were$ eligible.$ Men$ with$ pre-existing$ vascular$ conditions$ or$
history$of$VTE$were$included,$with$the$exception$of$a$cerebrovascular$event$within$3$
months$ prior$ to$ study$ enrolment.$Other$ exclusion$ criteria$ were$ prior$ oestrogen$
therapy$ or$ other$ active$ malignancy$ within$ the$ last$ 3$ years.$ $ Patients$had$ either$
declined$ docetaxel$ chemotherapy$or$ felt$ to$ be$ inappropriate$ candidates$ for$
chemotherapy$given$their$performance$status.$$
Treatment$
Transdermal$ Evorel®$ oestrogen$ patches$ delivering$ 50mcg$ oestradiol/24hours$ were$
given$to$all$patients.$ GnRH$analogues$and$steroids$were$discontinued$at$ the$start$of$
the$ study.$ Patients$ who$ had$ been$ on$ long$ periods$ of$ steroids$ were$ reduced$ to$
maintenance$levels.$All$patients$were$started$on$Aspirin$75mg$daily$unless$previously$
Transdermal*oestrogen*in*prostate*cancer*
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established$ on$ anti-platelet$ therapy.$ All$ patients$ received$ prophylactic$ Ranitidine$
(150mg$twice$daily).$
$
Baseline$ investigations$ included$ a$ chest$ radiograph,$ electrocardiogram$ and$ a$ bone$
scan.$$
$
Blood$tests$included$full$blood$count,$urea$and$electrolytes,$liver$function,$LDH,$PSA,$
testosterone,$LH,$FSH,$SHBG,$and$oestradiol$levels.$PSA$levels$were$checked$every$28$
days.$ A$ rise$ of$ >5μg/l$ triggered$ a$ repeat$ test$ 7-14$ days$ later.$ If$ this$ rise$ was$
confirmed,$ the$ Evorel®$ dose$ was$ increased$ initially$ to$ 100mcg/24$ hours$ then$ to$
200mcg/24hrs$and$finally$to$ 300mcg/24hrs.$At$the$start$of$ each$ course,$weight$and$
ECOG$ performance$ status$ were$ recorded.$ If$ there$ was$ further$ PSA$ progression$ or$
symptomatic$ progression$ at$ any$ point,$ patients$ were$ taken$ off$ the$ transdermal$
patch.$ Patients$ without$ contra-indication$ due$ to$ thrombo-embolism$ were$ offered$
diethylstilbestrol$1mg/day$following$discontinuation$of$TDE.$
$
Patients$ were$ reviewed$ every$ 28$ days$ during$ treatment$ and$ then$ 3-monthly$ for$ 1$
year.$Subsequent$follow-up$was$at$the$treating$clinician’s$discretion.$$
$
Transdermal*oestrogen*in*prostate*cancer*
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Patients$completed$the$European$Organisation$for$Research$and$Treatment$of$Cancer$
QLQ$C-30$ questionnaire$ and$ PR25$ prostate$ specific$ questionnaires$ to$ assess$ quality$
of$life$outcomes.$$
$
All$patients$gave$written$informed$consent$and$the$study$was$approved$by$the$local$
Ethics$ Committee.$ The$ recruitment$ period$ for$ this$ study$ was$ between$ 2004$ and$
2010.$
$
Statistics$
Endpoints$ were$ measured$ on$ an$ intention-to-treat$ principle.$ The$ primary$ endpoint$
was$ PSA$ response$ rate$ as$ defined$ by$ consensus$ criteria$(18).$ Secondary$ endpoints$
were$ incidence$ of$ thromboembolic$ events$ and$ progression$ free$ survival.$ Statistical$
considerations$indicated$that$ an$ open$study$of$14$ patients$ was$ required$ initially$ for$
95%$ chance$ of$ detecting$ at$ least$ one$ PSA$ response$ (>50%$ reduction$ of$ PSA$
maintained$for$one$month).$If$one$response$was$seen$the$trial$size$would$increase$to$
21$and$to$40$if$further$responses$were$seen$(19).$Stata$statistical$software$was$used$
for$all$statistical$analyses.$$
$
$
$ $
Transdermal*oestrogen*in*prostate*cancer*
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Results$
Patients$
In$ this$ two$centre$ study,$ 41$ patients$ were$ enrolled$in$ total.$ One$ patient$ withdrew$
prior$ to$ commencing$ therapy.$ Baseline$ patient$ characteristics$ are$ given$ in$ Table$ 1.$
Median$ age$ at$ enrollment$ was$ 76$years$ (inter$ quartile$ range$ 72-81).$ 26$ patients$
(65%)$ had$ an$ ECOG$ PS$ of$ 0-1,$ and$ 12$ patients$ (30%)$ 2-3.$ Data$ was$ missing$ for$ 2$
patients.$ Prior$ to$ receiving$ Evorel®,$ all$ patients$ had$ received$ GnRH$ analogues$ or$
undergone$bilateral$orchidectomy.$39$ patients$ (97%)$ received$ prior$steroid$therapy;$
1$ individual$had$an$absolute$ contraindication$ to$ steroids$ due$ to$ ongoing$
osteomyelitis.$No$patients$had$received$prior$chemotherapy.$
$
At$baseline,$the$median$PSA$measured$151ng/dl.$35$patients$(88%)$had$evidence$of$
bony$metastases.$All$ patients$ were$biologically-castrate$ except$ for$2$ (with$ elevated$
serum$ testosterone$ 2.2$ and$ 5.7nmol/l).$ These$ 2$ patients$ did$ not$ meet$ eligibility$
criteria$but$were$included$according$to$intention-to-treat$analysis.$Median$time$from$
diagnosis$ to$ development$ of$ castration$ resistant$ disease$ was$ 38$ months$ (inter$
quartile$range$20-67$months).$The$median$time$on$corticosteroids$prior$to$the$study$
was$ 4.5$ months$ (interquartile$ range$ 2.5-7.5$months).$ The$ median$ time$ from$
Transdermal*oestrogen*in*prostate*cancer*
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castration$resistant$disease$to$entry$to$the$study$was$12$months$(inter$quartile$range$
7.2-18$months).$$
$
Castration$was$maintained$in$all$patients$throughout$the$study$with$the$exception$of$
the$patient$with$the$baseline$serum$testosterone$of$5.7nmol/l.$
$
Table$ 1:$Baseline$ characteristics$ of$ patients$ receiving$ transdermal$ estradiol$ at$
treatment$randomisation:$
$
Number$of$patients$
40$
Median$age$(range)$
76$(58-87)$
Median$ time$ from$ castration$ resistance$ to$ starting$ TDE$
(range),$months$
12$(2-32)$
Median$duration$on$dexamethasone$(range),$months$
5$(1-17)$
ECOG$Performance$status$$
$$
0$
7/38$(18%)$
1$
20/38$(53%)$
2$
8/38$(21%)$
3$
2/38$(5%)$
Median$PSA$(ng/dL)$(range)$
151$(25-1386)$
Median$alkaline$phosphatase$level$(range)$
135$(39-2187)$
Median$haemoglobin$level$(g/dL)$(range)$
11.1$(8.3-16.4)$
Gleason$score$at$diagnosis$
$$
<8$
18/40$
8-10$
$
$
$
$
14/40$
NA$
8/40$
$
$
Presence$of$bony$metastases$$
35/40$(88%)$
$
$
Previous$therapy$
$
$
$
$
$
$
GnRH$agonist$
39/40$(98%)$
Bilateral$orchiectomy$
1/40$(3%)$
Steroid$therapy$
39/40$(97%)$
$
$
Transdermal*oestrogen*in*prostate*cancer*
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Toxicity$
After$4$months$on$treatment,$self-reported$gynaecomastia$had$increased$from$4%$to$
58%$(p=0.001),$however$hot$ flushes$ had$reduced$from$ 25%$ to$8%$(p=0.03).$ Nausea$
reporting$increased$from$ 10%$ to$18%$(p=0.05)$ (see$ Table$2).$There$were$no$ venous$
thrombo-embolic$ events.$ There$ was$ one$ vascular$ event$ (retinal$ artery$ occlusion).$
There$ were$ no$ skeletal$ events$ and$ no$ patients$ were$ on$ i.v.$ bisphosphonates$ or$
denosumab$during$the$study.$There$were$no$treatment$related$deaths.$$
$
Table$ 2:$ Symptoms$ reported$ at$ baseline$ and$ after$ 4$ months$ on$ treatment$
(EORTC-QLQ-C30$and$EORTC-QLQ-PR25):$
$
$
$
$
$
$
$
$
$
Oestradiol$and$Sex$Hormone$Binding$Globulin$
Increasing$TDE$dose$resulted$in$increasing$oestradiol$and$SHBG$concentrations$across$
all$ groups$(p<0.001).$By$ the$ end$ of$ treatment$ 39$ patients$ (97.5%)$ went$ onto$
!
At!baseline!
After!4!months!on!study!
!
!
!
Hot!flushes!
(7/28)!25%!
(2/26)!!8%!!!!!!!!!!!!!(p=0.03)!
Gynaecomastia!
(1/28)!4%!
(15/26)!!58%!!!!!!!!(p=0.001)!
Loss!of!masculinity!
(11/28)!39%!
(9/26)!!35%!!!!!!!!!!(p=0.29)!
Insomnia!
(11/31)!35%!
(11/27)!!42%!!!!!!!!(p=0.19)!
Nausea!and!vomiting!
(3/31)!10%!
(5/27)!!18%!!!!!!!!!!(p=0.05)!
Diarrhoea!
(3/30)!10%!
(3/27)!13%!!!!!!!!!!!(p=0.81)!
Constipation!
(5/29)!17%!
(9/27)!33%!!!!!!!!!!!(p=0.04)!
Anorexia!
(4/31)!14%!
(9/27)!33%!!!!!!!!!!!(p=0.02)!
Fatigue!
(13/31)!41%!
(15/27)!55%!!!!!!!!!(p=0.02)!
Dyspnoea!
(8/31)!26%!
10/27)!38%!!!!!!!!!!(p=0.03)!
Pain!
(11/31)!36%!
(14/27)!51%!!!!!!!!!(p=0.02)!!!!!!!!
Weight!loss!
(4/29)!14%!
(2/24)!!8%!!!!!!!!!!!!(p=0.69)!!!!!!!!!!!!!!!!
Weight!gain!
(6/29)!21%!
(3/26)!!12%!!!!!!!!!!(p=0.37)!
Oedema!
(8/29)!28%!
(12/27)!44%!!!!!!!!!(p=0.05)!
Transdermal*oestrogen*in*prostate*cancer*
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100mcg/day$patch,$33$patients$(82.5%)$onto$200mcg/day$and$24$patients$(60%)$went$
onto$300mcg/day$patch$(Table$3).$
$
Table$3:$PSA,$estradiol,$SHBG,$testosterone,$LH/FSH$at$start$of$increasing$TDE$dose:$
$
$
50mcg/day$
100mcg/day$
200mcg/day$
300mcg/day$
End$of$
treatment$$
$
$
$
$
n$
40$
39$
33$
24$
40$
Median$PSA$
(mg/ml)$
151$$
(25-1386)$
149$$
(42-2135)$
160$$
(15-1777)$
163$$
(14-1506)$
441$$
(21.8-2650)$
Median$plasma$
estradiol$
(pg/ml)$
41$$
(0-137)$
117$$
(25-323)$
187$$
(66-1109)$
577$$
(135-1801)$
573$$
(37-3094)$
Median$plasma$
SHBG$(nmol/l)$
$$
$
40$(14-70)$
54$(18-148)$
63$(17-113)$
76$(42-120)$
76$(40-157)$
Plasma$
testosterone$
(nmol/l)$
$
0.7$(0.4-5.7)$
0.7$(0.4-4.6)$
0.6$(0.4-4.3)$
0.6$(0.2-2.5)$
0.7$(0.4-2.1)$
LH$(IU/l)$
$
0.3$$
(0.1-23.2)$
0.3$$
(0.1-17.3)$
0.3$$
(0.2-15.8)$
0.2$$
(0.1-4.8)$
0.2$$
(0.1-0.5)$
FSH$(IU/l)$
3.8$$
(1.4-83.7)$
3.0$$
(0.2-29.2)$
1.4$$
(0.2-33.1)$
0.5$$
(0.2-6.2)$
0.2$$
(0.1-2.5)$
$
Transdermal*oestrogen*in*prostate*cancer*
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PSA$Change$
5/40$patients$ (13%)$ had$>50%$ reduction$for$ at$ least$1$ month$at$ any$ TDE$ dose.$ The$
median$ progression-free$ survival$ was$ 4.6$ months$ (95%$ CI$ 1.7$ to$ 6.2$ months).$ 2/39$
patients$ (5%)$ had$ a$ confirmed$ PSA$ reduction$ >50%$ at$ 50mcg/day$ and$ a$ further$ 2$
patients$(5%)$at$100mcg/day.$There$were$no$reductions$in$PSA$at$200mcg/day.$1/24$
patients$(4.3%)$ had$ a$ reduction$ of$ >50%$ at$ 300mcg/day$(Figure$ 1).$Correlation$ was$
seen$between$a$rise$in$ SHBG$ and$PSA$decline$as$well$as$between$ plasma$ oestradiol$
and$PSA$response$except$at$50mcg/day.$
$
The$ median$ maximum$ change$ in$ PSA$ was$ -21%$ (range$ -94.8$ to$ +242.7%).$ The$
percentage$achieving$PSA$control$i.e.$stable$or$reduction$in$PSA$for$at$least$1$month$
was$53%$ (21/40$ patients)$at$ 50mcg/day,$ 53%$(21/39$patients)$ at$ 100mcg/day,$52%$
(17/33$ patients)$ at$ 200mcg/day$ and$ 50%$ (12/24$ patients)$ at$ 300mcg/day$ and$ 55%$
(22/40$ patients)$ as$ a$whole.$ 18$ patients$ (45%)$ developed$ symptomatic$progression$
and$dropped$out$prior$to$maximum$dose$escalation.$
$
$
$
$
$
$
Transdermal*oestrogen*in*prostate*cancer*
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*
Figure$1$-$Waterfall$plots$for$the$changes$in$PSA$for$each$dose$of$transdermal$
oestradiol:$Graphs$demonstrate$respective$PSA$changes$at$(a)$50,$(b)$100,$(c)$200$and$
(d)$300$mcg$of$oestradiol.$
$
-100
-50
0
50
100
150
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37
(b)
-100
0
100
200
300
400
1357911 13 15 17 19 21 23 25 27 29 31 33
(c)
-100 .0
-50. 0
0.0
50 .0
10 0.0
15 0.0
20 0.0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
(d)
-100
-50
0
50
100
150
200
250
1357911 13 15 17 19 21 23 25 27 29 31 33 35 37 39
(a)
Transdermal*oestrogen*in*prostate*cancer*
18*
*
Survival$
Median$time$on$treatment$measured$5.5$months$(4.6-8.6$months$95%$C.I.).$Median$
survival$was$19.3$months$(interquartile$range$5.2-16.7$months).$Patients$with$normal$
alkaline$phosphatase$had$significantly$longer$time$on$treatment$and$overall$survival$
(OS)$ 9.1$ versus$ 4.2$ months$(p=0.0005)$ and$ 24.5$ versus$ 13.1$ months$ (p=0.001)$
respectively.$$
$
Time$on$treatment$and$OS$were$also$ significantly$longer$ in$patients$whose$ baseline$
Hb$was$greater$than$the$cohort$median:$8.15$months$vs$ 4.65$months$(p=0.005)$and$
24$vs$13.1$months$(p=0.066)$respectively.$$
$
Patients$with$baseline$PSA$less$than$the$median$also$had$a$longer$time$on$treatment$
and$ OS:$ 8.7months$ vs$ 4.35$ months$ (p=0.007)$ and$ 24.5$ vs$ 9.5$ months$ (p=0.0008)$
respectively.$
$
Diethylstilbestrol$
20$patients$received$diethylstilbestrol$post$TDE.$16$(80%)$had$a$decline$in$PSA$and$10$
(50%)$ had$ a$ >50%$ decline.$The$ median$ survival$ from$ the$ start$ of$ diethylstilbestrol$
Transdermal*oestrogen*in*prostate*cancer*
19*
*
was$46$months$in$those$who$had$a$50%$response$(range$6.2$–$NR)$vs$6.9$months$for$
those$who$did$not$(range$1.6-26.3)$($p=0.13)$
$
Quality$of$Life$
Mean$ standardized$ Quality$ of$ Life$ (QOL)$ scores$ initially$deteriorated$ on$ treatment$
compared$ to$ baseline$(QOL$ global$ score$ =$ 55.3$ at$ start$ of$ study,$ 44.7$ at$ 1$ month,$
p=0.04)$but$this$was$not$significant$at$4$months$of$treatment$(QOL$global$score$=$46,$
p=0.18).$In$addition,$hot$flushes$were$significantly$reduced$by$the$treatment.$
$$
Transdermal*oestrogen*in*prostate*cancer*
20*
*
Discussion$
Traditionally$ the$ hormonal$ targets$ for$ prostate$ cancer$ have$ focused$ on$ negating$
androgen$ action;$ however$ recent$ evidence$ from$ epidemiological$and$experimental$
data$have$elucidated$a$role$of$oestrogens$in$prostate$development$and$progression.$
The$prostate$expresses$both$oestrogen$receptor$alpha$(E)$and$oestrogen$receptor$
beta$(ERβ)$and$the$mechanism$of$action$of$oestrogen$in$prostate$cancer$is$likely$to$be$
multi-factorial$(20).$Most$evidence$suggests$that$ERα$mediates$the$harmful$effects$of$
oestrogen$ in$ the$ prostate$(21).$ Furthermore,$ ERα$ has$ been$ correlated$ with$ the$
tumour$ promoting$ function$ of$ TMPRSS2-ERG$ fusion,$ a$ major$ driver$ of$ prostate$
carcinogenesis$(22).$ In$ addition,$ the$ progressive$ emergence$ of$ ERα$ and$ ERα-
regulated$genes$during$prostate$cancer$progression$and$hormone$refractory$ disease$
suggests$that$these$tumours$can$bypass$the$AR$by$using$oestrogens$for$their$growth$
(21).$The$role$of$ERβ$in$the$prostate$remains$unclear$with$most$evidence$suggesting$
that$ ERβ$ is$ tumour$ suppressive$(23),$ however,$there$ is$ increasing$ evidence$ that$
isoforms$of$ERβ$may$be$oncogenic$(24,$25).$Finally,$it$has$been$shown$that$oestradiol$$
suppresses$tissue$ growth$ in$ vitro$ via$ ER-independent$ $mechanisms$ as$ well$ (26).$
Clinical$ trials$ using$oestrogen$ receptor-selective$ agents$ have$ not$ shown$ any$
improvements$in$clinical$outcomes$so$far$(20).$$
$
Transdermal*oestrogen*in*prostate*cancer*
21*
*
Our$cohort$of$patients’$response$to$TDE$was$modest$but$significant.$This$group$had$
been$pre-treated$with$GnRH$analogues$and$steroid$therapy$and$had$advanced$cancer$
as$demonstrated$by$resistance$to$castrate$levels$of$testosterone$and$a$median$PSA$of$
151.$A$significant$proportion$(26%)$were$Performance$Status$(PS)$2-3$and$were$thus$
inappropriate$for,$or$had$declined$Docetaxel$chemotherapy.$The$majority$of$patients$
had$ been$ on$ treatment$ for$ some$ time,$ with$ median$ time$ from$ diagnosis$ to$
development$of$castration$resistant$disease$of$38$months.$
$
A$ PSA$ response$ of$ >50%$ was$ seen$ in$ 13%$ of$ patients$ at$ any$ TDE$ dose.$ In$ 56%$ of$
patients,$TDE$use$at$any$dose$was$associated$with$either$ a$fall$ in$ PSA$ or$ stable$PSA.$
This$study$commenced$prior$to$the$adoption$of$PCWG-2$criteria$(6),$which$advises$12$
weeks$ of$ drug$ therapy$ prior$ to$ a$ confirmed$ rise$ in$ PSA$ rather$ than$ the$ 35-42$days$
followed$in$this$study.$This$may$have$resulted$in$underestimation$of$response$to$TDE.$$
$
Median$ time$ on$ treatment$ was$5.5$ months$ while$ the$ median$ time$ to$ progression$
using$ Kaplan-Meier$ estimates$ was$ 4.6$ months$ (1.7-6.2$ months).$ Median$ overall$
survival$ for$ this$ cohort$ was$ 19.3$ months$which$ compares$ favourably$ with$ overall$
survival$ in$ patients$ with$ metastatic$ CRPC$ receiving$ Docetaxel$ in$ the$ TAX-327$ trial$
(27).$Some$better$prognostic$groups$were$identified:$patients$with$a$ normal$alkaline$
phosphatase,$ or$ Hb$ >median$ were$ predictive$ factors$ for$ longer$ time$ on$ treatment$
Transdermal*oestrogen*in*prostate*cancer*
22*
*
and$greater$overall$survival.$In$those$ patients$ who$had$a$ 50%$PSA$response,$overall$
survival$was$excellent$at$46$months.$
$
Oestrogens$ are$ also$ known$ to$ have$ bone$protective$ effects$(28).$ Prostate$ cancer$
patients$with$a$high$ incidence$ of$bony$metastases$ and$ prolonged$LHRH$ agonist$ use$
are$ at$ high$ risk$ of$ pathological$ fractures$ (4).$ Reassuringly$ no$ skeletal$ events$ were$
recorded$in$this$study.$
$
Oral$DES$has$been$shown$to$have$activity$in$CRPC$(29).$$Shamash$ et$al,$conducted$a$
Phase$III$trial$using$immediate$or$deferred$DES$in$conjunction$with$dexamethasone$in$
CRPC$(30).$ Immediate$ DES$ was$ not$ superior$ to$ delayed$ DES$ with$ regards$ to$ PSA$
response$ rate$ or$ progression$ free$ survival$ (RR$ 68%$ immediate$ vs$ 64%$ deferred,$
p=0.49).$Given$the$high$incidence$of$VTE$with$immediate$DES$(22%$vs$11%),$DES$use$
was$not$recommended$until$failure$of$dexamethasone.$In$our$cohort,$there$was$one$
vascular$ event$ recorded;$a$ retinal$ artery$ occlusion$which$ was$ not$ a$ VTE.$ This$
supports$the$ belief$that$ TDE$has$a$ lower$ VTE$ side$ effect$ profile$than$ DES.$TDE$ may$
therefore$ be$ an$ option$ prior$ to$ DES$ therapy$ and$ a$ trial$ in$conjunction$with$
dexamethasone$may$be$appropriate.$$
$
Transdermal*oestrogen*in*prostate*cancer*
23*
*
Furthermore,$ there$ was$ significant$ response$ to$ DES$ after$ TDE$ treatment$ indicating$
there$possible$lack$of$cross$resistance$between$these$two$treatments.$The$activity$of$
DES$ after$ TDE$ suggests$ that$ the$ mechanism$ of$ action$ of$ transdermal$ and$ oral$
oestrogens$upon$CRPC$is$ not$ equivalent$and$ warrants$further$investigation.$There$is$
evidence$ of$ endocrine$ re-sensitisation$on$ discontinuing$ GnRH$ analogues$ whilst$ on$
alternative$therapy.In$another$study$by$Shamash$et$al,$for$example,$there$is$evidence$
of$ re-sensitisation$to$ hormonal$ therapy$ by$ discontinuing$ GnRH$ analogues$ during$
docetaxel$chemotherapy$(31).$Therefore,$ it$is$ possible$that$this$ re-sensitization$also$
applies$ to$ discontinuation$ of$ GnRH$ due$ to$ oestrogen$ use$ and$ would$ be$ very$
interesting$to$study$in$more$detail.$$
$
In$addition,$in$this$study$we$have$shown$that$TDE$affected$SHBG$in$a$dose-dependent$
fashion,$ and$ increased$ SHBG$ levels$ were$associated$ with$ a$ PSA$ response.$ This$
suggests$that$ SHBG$ may$ play$a$ role$ in$ driving$ the$ prostate$ cancer$ response$and$
correlates$with$the$fact$that$at$the$lowest$dose,$a$rise$in$SHBG$correlated$with$a$fall$
in$ PSA.$ Alterations$ in$ SHBG$ can$ alter$ the$ equilibrium$ between$ bound$ and$ free$
androgens$ affecting$ the$ availability$ of$ androgens$ to$ induce$ androgen$ receptor$
responses$ (32)$and$ this$ may$ be$ a$pathway$ for$ oestrogen$ to$ exert$ its$ influence$ on$
CRPC.$ The$ significance$ of$ SHBG$ remains$ under-investigated$ in$ CRPC$but$ the$
association$seen$in$this$trial$suggests$it$should$be$investigated$further.$
Transdermal*oestrogen*in*prostate*cancer*
24*
*
Increasing$ the$ TDE$ dose$ above$ 200mcg/day$ did$ not$ increase$ the$ PSA$ response$
observed.$The$number$of$patients$included$in$the$trial$was$small$and$a$dose$response$
may$ have$ been$ observed$ had$ more$ patients$ been$ included.$ In$ addition,$ it$ may$ be$
that$ for$ some$ patients$ where$ a$ PSA$ response$ at$ a$ lower$ dose$ was$ not$ seen,$
resistance$to$TDE$had$already$ developed$ and$this$could$not$be$ overcome$ with$dose$
increases.$
$
There$ are$ a$ number$ of$ limitations$ to$ our$ study.$ This$ was$ a$ small$ Phase$ II$ study$
involving$ 40$ patients$ in$ 2$ institutions$ and$ drawing$ conclusions$ as$ to$ the$ efficacy$ of$
TDE$in$the$wider$population$of$patients$with$CRPC$is$difficult.$In$addition,$there$was$
no$$use$of$routine$radiological$assessment$during$therapy.$In$fact,$in$many$studies$of$
second$generation$agents,$PSA$response$is$still$an$important$and$easy$way$to$assess$
early$response$however$it$is$clear$that$benefit$is$sometimes$seen$when$PSA$remains$
stable$or$ only$ slowly$increases.$ The$ dose$ titration$ in$the$ study$design$ meant$that$it$
was$much$harder$to$show$large$PSA$responses$as$TDE,$was$only$increased$if$PSA$rose.$
In$addition,$patients$came$off$the$study$ with$predefined$rises$in$PSA$which$may$not$
have$been$clinically$significant$again,$leading$to$possible$under$reporting$of$efficacy.$
Furthermore,$this$study$was$conducted$prior$to$the$routine$use$of$second$generation$
anti-androgens$and$ clearly$ it$ would$ be$ interesting$ to$ know$ whether$ there$ was$ any$
cross-resistance$ between$ them$ and$ transdermal$ oestradiol.$ None$ of$ the$ patients$
Transdermal*oestrogen*in*prostate*cancer*
25*
*
received$ prior$ chemotherapy$for$ castration-resistant$ disease$ which$would$ also$ be$
standard$nowadays$for$fit$patients.$
$
Finally,$clinical$trials$are$currently$investigating$the$use$of$TDE$in$metastatic$prostate$
cancer$in$the$hormone$sensitive$setting.$For$example,$the$PATCH$trial$(NCT00303784)$
compares$ the$ efficacy$ and$ safety$ of$ TDE$ vs$ GnRH$ analogues$ in$ men$ with$ locally$
advanced$ and$ metastatic$ prostate$ cancer$ and$ has$ so$ far$ recruited$ >2000$patients$
(33).$ The$ initial$ pilot$ phase$ showed$ that$ TDE$ achieved$ equivalent$ castrate$ levels$ of$
testosterone$ to$ GnRH$ analogues$ without$ the$ previously$ observed$ rates$ of$
cardiovascular$ toxicity$ seen$ with$ oral$ oestrogen$ (15).$ Furthermore,$ the$ STAMPEDE$
trial$(NCT00268476)$now$includes$a$ ‘TDE$ arm’$since$2017$and$this$will$compare$TDE$
to$ ADT$and$ together$ with$ the$ PATCH$ trial$ will$ be$ able$ to$ define$ the$ role$ of$ this$
treatment$in$metastatic$hormone$sensitive$prostate$cancer$(34).$
$
Conclusion$
This$ study$demonstrated$ that$ TDE$ is$ a$ low$ toxicity$ treatment$ that$ may$ provide$
control$ of$ CRPC$ after$ failure$ of$ steroid$ therapy$and$ that$ a$ dose$ of$ 200mcg/day$ -$
300mcg/day$has$an$acceptable$efficacy$/$toxicity$profile.$$The$low$toxicity$and$lack$of$
cross$ reaction$ with$ DES$ suggest$ it$ is$ a$ reasonable$ pre-DES$ therapy$ and$ could$ be$
considered$ as$ an$ alternative$ to$ novel$ anti-androgen$ therapies$ or$ as$ alternative$ to$
Transdermal*oestrogen*in*prostate*cancer*
26*
*
Docetaxel$chemotherapy$particularly$in$less$fit$patients.$The$most$significant$adverse$
effect$ is$ gynaecomastia.$ $ The$ correlation$ of$ SHBG$ levels$ with$ TDE$dose$ and$ PSA$
response$ suggest$ that$ modulation$ of$ SHBG$ level$ by$ oestrogens$ may$ play$ an$
important$role$in$the$effect$of$oestrogens$on$CRPC.$In$addition,$the$finding$ that$DES$
remains$active$after$TDE$suggests$differing$mechanisms$of$action$on$CRPC$dependent$
on$the$ route$ given.$$ It$would$ therefore$appear$that$ TDE$ is$ a$ safe$ and$valid$ therapy$
and$that$there$is$much$more$to$learn$about$the$role$of$oestrogens$in$CRPC.$$
$
$
Clinical$practice$points$
Oral$systemic$oestrogen$treatment,$in$the$form$of$diethylstilbestrol$(DES),$was$widely$
used$ in$ prostate$ cancer$ and$ castration-resistant$ disease.$Their$ use,$ however,$ was$
associated$with$increased$risk$of$cardiovascular$and$thromboembolic$events$resulting$
from$ the$ first-pass$ metabolism$ in$ the$ liver.$ TDE$ avoids$ this$ effect$ and$ offers$ an$
alternative$and$potentially$safer$means$of$androgen$suppression.$
TDE$ used$ in$ this$ population$ of$ patients$ with$ CRPC$ post$ GHRHa$ and$ DES$ treatment$
was$found$to$be$safe$and$well$tolerated.$Importantly$TDE$lead$to$PSA$decline$of$>50%$
in$13%$of$patients$with$a$median$progression-free$survival$of$4.6$months.$$
Optimal$ inhibition$ of$ the$ AR$ signaling$ pathway$ remains$ an$ important$ target$in$ the$
setting$of$CRPC$and$the$use$of$TDE$as$an$alternative$modality$of$maintaining$castrate$
Transdermal*oestrogen*in*prostate*cancer*
27*
*
levels$of$testosterone$is$a$possible$option$especially$for$the$older$and$less$fit$patients$
who$ might$ not$ tolerate$ chemotherapy$or$ second-generation$ anti-androgens$ and$
should$always$be$considered.$These$results$are$also$significant$in$the$rapidly$evolving$
treatment$setting$ of$metastatic$ castration-resistant$ prostate$cancer.$Given$that$ this$
study$was$conducted$during$a$period$where$second-generation$anti-androgens$were$
not$approved$or$available,$the$optimum$treatment$sequence$of$TDE$and$other$novel$
that$modulate$the$AR$pathway$is$currently$unclear$and$further$trials$will$need$to$be$
performed$to$determine$this.$ $
Transdermal*oestrogen*in*prostate*cancer*
28*
*
Declarations$of$interests$
None$Declared$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
Transdermal*oestrogen*in*prostate*cancer*
29*
*
Funding$
The$Orchid$Cancer$Appeal$funded$the$clinical$trials$nurse.$
$
$ $
Transdermal*oestrogen*in*prostate*cancer*
30*
*
Acknowledgments:$$
We$would$like$to$thank$ Dr$S.$Gibbs,$ consultant$ clinical$oncologist,$ Barking$ Havering$
and$Edbridge$NHS$trust$for$referring$patients$for$this$study.$$
$
$$
Transdermal*oestrogen*in*prostate*cancer*
31*
*
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30.* Shamash* J,* Powles* T,* Sarker* SJ,* Protheroe* A,* Mithal* N,* Mills* R,* et* al.* A* multi-centre*
randomised* phase* III* trial* of* Dexamethasone* vs* Dexamethasone* and* diethylstilbestrol* in*
castration-resistant* prostate* cancer:* immediate* vs* deferred* Diethylstilbestrol.* Br* J* Cancer.*
2011;104(4):620-8.*
31.* Shamash* J,* Davies* A,* Ansell* W,* McFaul* S,* Wilson* P,* Oliver* T,* et* al.* A* phase* II* study*
investigating* the* re-induction* of* endocrine* sensitivity* following* chemotherapy* in* androgen-
independent*prostate*cancer.*Br*J*Cancer.*2008;98(1):22-4.*
Transdermal*oestrogen*in*prostate*cancer*
33*
*
32.* Rosner* W,* Hryb* DJ,* Khan* MS,* Nakhla* AM,* Romas* NA.* Sex* hormone-binding* globulin:*
anatomy*and*physiology*of*a* new* regulatory* system.* The*Journal*of*steroid*biochemistry*and*
molecular*biology.*1991;40(4-6):813-20.*
33.* Prostate*Adenocarcinoma*TransCutaneous*Hormones*(PATCH).*
34.* Systemic* Therapy* in* Advancing* or* Metastatic* Prostate* Cancer:* Evaluation* of* Drug*
Efficacy*(STAMPEDE).*
*
Clinical'practice'points'
Oral'systemic'oestrogen'treatment,'in'the'form' of'diethylstilbestrol' (DES),'was'
widely' used' in' prostate' cancer' and' castration-resistant' disease.'Their' use,'
however,' was' associated' with' increased' risk' of' cardiovascular' and'
thromboembolic'events'resulting'from'the'first-pass'metabolism'in'the'liver.'TDE'
avoids' this' effect' and' offers' an' alternative' and' potentially' safer' means' of'
androgen'suppression.'
TDE'used'in'this'population'of'patients'with'CRPC'post'GHRHa'and'DES'treatment'
was'found'to'be'safe'and'well'tolerated.'Importantly'TDE'lead'to'PSA'decline'of'
>50%'in'13%'of'patients'with'a'median'progression-free'survival'of'4.6'months.''
Optimal'inhibition'of'the'AR'signaling'pathway'remains'an'important'target'in'the'
setting' of' CRPC'and' the' use' of' TDE'as' an' alternative' modality' of' maintaining'
castrate'levels'of'testosterone' is' a' possible' option'especially' for'the'older' and'
less'fit'patients'who'might'not'tolerate'chemotherapy'or'second-generation'anti-
androgens'and'should'always'be'considered.'These'results'are'also'significant'in'
the'rapidly'evolving'treatment'setting'of'metastatic'castration-resistant'prostate'
cancer.'Given' that' this' study' was' conducted' during' a' period' where' second-
generation' anti-androgens' were' not' approved' or' available,' the' optimum'
treatment' sequence' of' TDE' and' other'novel' that'modulate' the' AR' pathway'is'
currently'unclear'and'further'trials'will'need'to'be'performed'to'determine'this.!
*Clinical Practice Points
Microabstract
*
We*aimed*to*investigate*the*role*and*safety*of*transdermal*oestrogen*therapy*in*
castrate*resistant*prostate*cancer.*Within*this*dose*escalation*study*we*observed*
reduction*in*PSA*levels*at*all*doses*used.*In*addition,*no*venous*thromboembolic*
events*were*detected*making*the*use*of*transdermal*oestradiol*a*safe*treatment*
option*for*a*subgroup*of*patients*with*castration-resistant*prostate*cancer.*
!
*Micro-Abstract
... Another treatment option is hormone therapy. Hormone therapy is a powerful and safe treatment that helps hormone receptor-positive tumours perform better clinically [101]. ...
... Researchers have looked into different drug combinations and schedules to lessen the adverse effects of the therapy. Smith et al. [101] found that transdermal E2 at a dose of 50 mcg/24 h resulted in a >50% decrease in PSA in 5 out of 40 steroid-resistant PCa patients (13%) after one month of treatment. The researchers stated that E2 stopped the PCa cells from growing by changing the function of the sex hormone-binding globulin through what is called an ER-independent pathway. ...
Article
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Castration-resistant prostate cancer, or CRPC, is an aggressive stage of prostate cancer (PCa) in which PCa cells invade nearby or other parts of the body. When a patient with PCa goes through androgen deprivation therapy (ADT) and the cancer comes back or worsens, this is called CRPC. Instead of androgen-dependent signalling, recent studies show the involvement of the estrogen pathway through the regulation of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in CRPC development. Reduced levels of testosterone due to ADT lead to low ERβ functionality in inhibiting the proliferation of PCa cells. Additionally, ERα, which possesses androgen independence, continues to promote the proliferation of PCa cells. The functions of ERα and ERβ in controlling PCa progression have been studied, but further research is needed to elucidate their roles in promoting CRPC. Finding new ways to treat the disease and stop it from becoming worse will require a clear understanding of the molecular processes that can lead to CRPC. The current review summarizes the underlying processes involving ERα and ERβ in developing CRPC, including castration-resistant mechanisms after ADT and available medication modification in mitigating CRPC progression, with the goal of directing future research and treatment.
... This original usage is now restricted because of the high risk for pathogenesis of breast, cervical, and vaginal cancers in daughters born from DES-prescribed mothers (Al Jishi and Sergi 2017; Gibson and Saunders 2014; Reed and Fenton 2013). In recent clinical applications, DES has been utilized for treatment of androgen-independent and castration-resistant prostate cancers as a secondary endocrine therapy (Sinha and Wilson 2018;Smith et al. 2020). In experimental studies, DES was applied to create an animal model for hyper-prolactinoma (Jindatip et al. 2018;Tun et al. 2019), and fetal exposure to DES was shown to alter sociosexual behaviors after maturation (vom Saal et al. 1995;Palanza et al. 1999bPalanza et al. , 1999a. ...
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Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, β, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRβ, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics.
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Background Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs). Methods DFOTs published from June 2016–December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions. Findings Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians’ assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally. Interpretation This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting. Funding EA has been supported to undertake this work as part of a PhD studentship from the 10.13039/501100000650Institute of Cancer Research within the 10.13039/501100000265MRC/10.13039/501100000272NIHR Trials Methodology Research Partnership. AM is supported by the 10.13039/501100000272National Institute for Health Research (NIHR) 10.13039/100014461Biomedical Research Centre at the 10.13039/100012139Royal Marsden NHS Foundation Trust, the 10.13039/501100000650Institute of Cancer Research and Imperial College.
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Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed.
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Prostate cancer is the commonest, non-cutaneous cancer in men. At present, there is no cure for the advanced, castration-resistant form of the disease. Estrogen has been shown to be important in prostate carcinogenesis with evidence resulting from epidemiological, cancer cell-line, human tissue and animal studies. The prostate expresses both estrogen receptor alpha and estrogen receptor beta. Most evidence suggests that estrogen receptor alpha mediates the harmful effects of estrogen in the prostate whereas estrogen receptor beta is tumour-suppressive, but trials of estrogen receptor beta-selective agents have not translated into improved clinical outcomes. The role of estrogen receptor beta in the prostate remains unclear and there is increasing evidence that isoforms of estrogen receptor beta may be oncogenic. Detailed study of estrogen receptor beta and estrogen receptor beta isoforms in the prostate is required to establish their cell-specific roles, in order to determine if therapies can be directed towards estrogen receptor beta-dependent pathways. In this review we summarise evidence on the role of estrogen receptor beta in prostate cancer and highlight areas for future research.
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Article
Background: The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Methods: Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. Results: The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Conclusions: Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation.
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Background: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. Methods: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. Results: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate?prednisone group than in the placebo?prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate?prednisone group than in the placebo?prednisone group. Conclusions: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Article
Metastatic castration-resistant prostate cancer remains a lethal disease despite considerable progress in systemic therapy over the past decade. The recent advances in genomic sequencing have improved the molecular classification of prostate cancer. The translation of genomic data into clinically relevant prognostic and predictive biomarkers to guide therapy is still in its infancy and therapies for castration-resistant prostate cancer are still used empirically. We discuss these genomic aberrations in more detail, focusing on androgen receptor signaling, ETS transcription factor gene rearrangements and PTEN loss. The incorporation of this genomic data within early phase clinical trials is evolving and may prove significant in advancing personalized care in prostate cancer.
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Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway.Oncogene advance online publication, 19 May 2014; doi:10.1038/onc.2014.115.
Article
Background: Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. Methods: In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. Findings: 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). Interpretation: Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. Funding: Cancer Research UK, MRC Clinical Trials Unit.