Adrenal carcinoma and pheochromocytoma - media.aiom.itmedia.aiom.it/userfiles/files/doc/AIOM-Servizi/slide/20180302MI_51... · What is the Concern with an Adrenal Incidentaloma? Presented

Adrenal carcinoma and pheochromocytoma

Salvatore Grisanti, Alfredo Berruti

Department of Medical Oncology

University of Brescia - Spedali Civili di Brescia

Milan, 02 March 2018 - Post ASCO-GU 2018

I am perfectly aware of the risk of being a speaker after lunch

Adrenocortical carcinoma (ACC)

Pheochromocytoma (PCC) & paraganglioma


Adrenal gland: physiology

The clinical management of ACC and PCC is complex because the clinician have to face two problems at the same time in most patients

• The neoplastic mass & metastases

• The endocrinological-associated disease (Cushing, etc …)

Two diseases in one


Milan, 02 February 2018 - Post ASCO-GU 2018

Endocrinology

Med. Treatment

Surg. Treatment

Radiol. Diagnosis

Adrenocortical Carcinoma: Finding the Wolf in Sheep’s Clothing

Presented By William Mayo-Smith at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

What is the Concern with an Adrenal Incidentaloma?


7 Imaging Phenotypes to differentiate benign & pathologic adrenal


7 Imaging features to differentiate benign from pathologic adrenal


Enhancement Patterns


Adrenocortical Carcinoma: Putting it Together



• Chi si deve trattare?

• Quale chirurgia?

Adrenal Tumors

Presented By Jonathan Coleman at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Adrenal Incidentalomas Indications for Surgery


Incidence of Adrenal Ca According to Tumor Size Review of 20 reported series and meta-analysis


Stage disposition in localized ACC

Curable (39%)

2%

19%

18%

61%

%


Role of surgery in ACC

Surgery is the mainstay of therapy and represents the only chance of cure


Survival according to completeness of resection MSKCC experience


Adrenocortical Carcinoma: Consensus in Treatment


Slide 17


Slide 18



Gronchi et al. JCO 2009

Adrenocortical Carcinoma 5-Year Survival Rates (%) from Reported Series


Which surgery?

• Two different approaches are possible for adrenalectomy:

• Open surgery adrenalectomy (OA)

• Laparoscopic adrenalectomy (LA)

• No prospective trials are available to determine which is the best strategy


Laparoscopic Adrenalectomy in ACC – Spillage and Recurrence Risks


Survival Analysis


Open surgery vs laparoscopic adrenalectomy?

Porpiglia et al. Eur Urol 2010

• Comparable recurrence-free survival in OA and LA groups

• Type of surgical treatment is not a prognostic factor


Peritoneal Dissemination A Complication of Laparoscopic Surgery

Presented By Antonio Fojo at 2017 ASCO Annual Meeting

Slide 6

Presented By Antonio Fojo at 2017 ASCO Annual Meeting

Laparoscopic vs Open: Meta-Analysis


OA vs LA: ESMO guidelines

• Open surgery with transperitoneal access is the standard treatment of all patients with localized (stage I–II) and local advanced stage (stage III) ACCs when complete resection can be achieved.

• Laparoscopic adrenalectomy is a safe and effective procedure for a selected group of patients with small ACCs (<8 cm) without preoperative evidence for invasiveness and adrenal masses (e.g. incidentalomas) that are judged as only potentially malignant.

ESMO guidelines. Ann Oncol 2012


Domanda ECM !

Pheochromocytoma Principles of Surgery



• Quali sindromi endocrine?

• Quale work-up?

• Quale trattamento? • Test genetici

Slide 9

Presented By Tobias Else at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Hormone excess in ACC

Hirsutism, deepening of the voice, breast atrophy, male pattern baldness, clitoral hypertrophy, oligomenorrhea, altered libido

Gynecomastia, breast tenderness, decreased libido, testicular atrophy

Severe hypertension, hypokaliemia

Lafemina et al. J Surg Oncol 2012


Cushing’s syndrome in ACC

• Secondary to corticosteroid (cortisol) excess

• Metabolic abnormalities:

• Glucose intolerance/Diabetes

• Osteoporosis/Fractures

• Hypertension

• Immunedeficiency (lymphocytotoxic effect of glucocorticoids)

• Psychiatric disorders


Adrenal Glands

Prognostic Roleof Overt Hypercortisolism in Completely Operated

Patients with Adrenocortical Cancer

Alfredo Berruti a,*, Martin Fassnacht b,g, Harm Haak c, Tobias Elsed, Eric Baudine,

Paola Speronef, Matthias Kroissg, Thomas Kerkhofsc, Andrew R. Williamsd, Arianna Arditoh,

Sophie Leboulleuxe, Marco Volantei, Timo Deutschbein g, Richards Feeldersj, Cristina Ronchi g,

Salvatore Grisanti a, Hans Gelderblomk, Francesco Porpiglia l, Mauro Papotti i,

Gary D. Hammer d, Bruno Alloliog, Massimo Terzoloh

aDepartment of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Spedali Civili Hospital, Brescia, Italy;bDepartment of Internal Medicine IV, University Clinic, Munich, Germany; cInternal Medicine, Maxima Medical Centre, Eindhoven, The Netherlands;dMetabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA; eEndocrine

Oncology and Nuclear Medicine, GustaveRoussy Institute, Villejuif, France; f Department of Oncology, University of Turin, Medical Oncology Unit, San Luigi

Gonzaga Hospital, Orbassano, Italy; gDepartment of Medicine I, Endocrine Unit, University Hospital of Wurzburg, Germany; hDepartment of Clinical and

Biological Sciences, University of Turin, Internal Medicine I, S. Luigi Gonzaga Hospital, Orbassano, Italy; i Department of Oncology, University of Turin,

Pathology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy; j ErasmusMC, Rotterdam, TheNetherlands; k Department of Clinical Oncology, Leiden University

Medical Center, Leiden, The Netherlands; l Department of Oncology, University of Turin, Urology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy

EUROPEAN UROLOGY 65 ( 2014) 832–838

avai lable at www.sciencedi rect .com

journal homepage: www.europeanurology.com

Article info

Article history:

Accepted November 4, 2013

Published online ahead of

pr int on November 13, 2013

Keywords:

Adrenocortical cancer

Adjuvant therapy

Cushing syndrome

Mitotane

Abstract

Background: Although prognosticparametersareimportant toguideadjuvant treatment,very

few havebeen identified in patientswith completely resected adrenocortical carcinoma(ACC).

Objective: To assess the prognostic role of clinical symptoms of hypercortisolism in a large

series of patients with completely resected ACC.

Design,setting,andparticipants: Atotal of 524patients followed at referral centersfor ACCin

Europe and the United States entered the study. Inclusion criteria were 18 yr of age, a

histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of

other malignancies and adjuvant systemic therapies other than mitotane.

Intervention: All ACCpatientswerecompletely resected, and adjuvant mitotane therapy was

prescribed at the discretion of the investigators.

Outcomemeasurementsand statistical analysis: The primary end point was overall survival

(OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of

adjuvant mitotane therapy according to cortisol secretion.

Resultsand limitations: Overt hypercortisolism wasobserved in197patients(37.6%).Patients

with cortisol excesswereyounger (p=0.002); no differenceaccording to sex and tumor stage

was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age,

tumor stage,and mitotanetreatment, theprognosticsignificanceof cortisol excesswashighly

significant for both RFS (hazard ratio [HR]: 1.30; 95%confidence interval [CI], 1.04–2.62;

p=0.02) and OS(HR: 1.55; 95%CI, 1.15–2.09; p=0.004). Mitotaneadministration wasassoci-

ated with a reduction of diseaseprogression (adjusted HR: 0.65; 95%CI, 0.49–0.86; p=0.003)

that did not differ according to the patient’s secretory status. A major limitation is that only

symptomaticpatientswereconsidered ashavinghypercortisolism,thusexcludinginformation

on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome.

Conclusions: Clinically relevant hypercortisolism is a new prognostic factor in patients with

completely resected ACC.Theefficacy of adjuvant mitotanedoesnot seem tobe influenced by

overt hypercortisolism.

# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. OncologiaMedica, AziendaOspedalieraSpedali Civili,PiazzaleSpedali Civili

1, 20123 Brescia, Italy. Tel. +39 030 3995410; Fax: +39 030 3700017.

E-mail address: [email protected] (A. Berruti).

0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.eururo.2013.11.006

Adrenal Glands

Prognostic Roleof Overt Hypercortisolism in Completely Operated

Patients with Adrenocortical Cancer

Alfredo Berruti a,*, Martin Fassnacht b,g, Harm Haak c, Tobias Elsed, Eric Baudine,

Paola Speronef, Matthias Kroissg, Thomas Kerkhofsc, Andrew R. Williamsd, Arianna Arditoh,

Sophie Leboulleuxe, Marco Volantei, Timo Deutschbein g, Richards Feeldersj, Cristina Ronchi g,

Salvatore Grisanti a, Hans Gelderblomk, Francesco Porpiglia l, Mauro Papotti i,

Gary D. Hammer d, Bruno Alloliog, Massimo Terzoloh

aDepartment of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Spedali Civili Hospital, Brescia, Italy;bDepartment of Internal Medicine IV, University Clinic, Munich, Germany; cInternal Medicine, Maxima Medical Centre, Eindhoven, The Netherlands;dMetabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA; eEndocrine

Oncology and Nuclear Medicine, Gustave Roussy Institute, Villejuif, France; f Department of Oncology, University of Turin, Medical Oncology Unit, San Luigi

Gonzaga Hospital, Orbassano, Italy; gDepartment of Medicine I, Endocrine Unit, University Hospital of Wurzburg, Germany; hDepartment of Clinical and

Biological Sciences, University of Turin, Internal Medicine I, S. Luigi Gonzaga Hospital, Orbassano, Italy; i Department of Oncology, University of Turin,

Pathology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy; j ErasmusMC, Rotterdam, TheNetherlands; k Department of Clinical Oncology, Leiden University

Medical Center, Leiden, The Netherlands; l Department of Oncology, University of Turin, Urology Unit, S. Luigi Gonzaga Hospital, Orbassano, Italy

EUROPEAN UROLOGY 65 ( 2014) 832–838

avai lable at www.sciencedi rect .com

journal homepage: www.europeanurology.com

Article info

Article history:

Accepted November 4, 2013

Published online ahead of

pr int on November 13, 2013

Keywords:

Adrenocortical cancer

Adjuvant therapy

Cushing syndrome

Mitotane

Abstract

Background: Althoughprognosticparametersareimportant toguideadjuvant treatment,very

few havebeen identified in patientswith completely resected adrenocortical carcinoma(ACC).

Objective: To assess the prognostic role of clinical symptoms of hypercortisolism in a large

series of patients with completely resected ACC.

Design,setting,andparticipants: Atotal of 524 patients followed at referral centersfor ACCin

Europe and the United States entered the study. Inclusion criteria were 18 yr of age, a

histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of

other malignancies and adjuvant systemic therapies other than mitotane.

Intervention: All ACCpatients werecompletely resected, and adjuvant mitotane therapy was

prescribed at the discretion of the investigators.

Outcomemeasurements and statistical analysis: The primary end point wasoverall survival

(OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of

adjuvant mitotane therapy according to cortisol secretion.

Resultsand limitations: Overt hypercortisolism wasobserved in 197patients(37.6%).Patients

with cortisol excesswereyounger (p=0.002); no differenceaccording to sex and tumor stage

was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age,

tumor stage, and mitotanetreatment, theprognostic significanceof cortisol excesswashighly

significant for both RFS (hazard ratio [HR]: 1.30; 95%confidence interval [CI], 1.04–2.62;

p=0.02) and OS(HR: 1.55; 95%CI, 1.15–2.09; p=0.004). Mitotaneadministration wasassoci-

ated with a reduction of disease progression (adjusted HR: 0.65; 95%CI, 0.49–0.86; p=0.003)

that did not differ according to the patient’s secretory status. A major limitation is that only

symptomaticpatientswereconsidered ashavinghypercortisolism,thusexcludinginformation

on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome.

Conclusions: Clinically relevant hypercort isolism is a new prognostic factor in patients with

completely resected ACC.Theefficacy of adjuvant mitotanedoesnot seem tobe influenced by

overt hypercortisolism.

# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. OncologiaMedica,AziendaOspedalieraSpedali Civili,PiazzaleSpedali Civili

1, 20123 Brescia, Italy. Tel. +39 030 3995410; Fax: +39 030 3700017.

E-mail address: [email protected] (A. Berruti).

0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.eururo.2013.11.006

Berruti et al. Eur Urol 2014, 65:832-838

Domanda ECM !


Diagnosis of ACC/PCC: ESMO/ENSAT proposed workup

ESMO guidelines. Ann Oncol 2012


Slide 14


Slide 15


Metirapone

Metyrapone is the fastest drug in controlling Cushing’s disease

Claps et al. Endocrine 2017


Abiraterone on biosynthesis of steroidal hormones

Veytsman et al. J Clin Oncol 2009


Abiraterone in Cushing’s syndrome: the Abacus trial


Genetic considerations


Slide 17


Slide 18



Strategies of treatment of PCC Adjuvant treatment of ACC Treatment of M+ ACC Neoadjuvant treatment of ACC

Malignant Phaeochromocytoma (and Paraganglioma) 2#

Presented By David Quinn at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

What is the prognosis of ACC?

Most of papers on ACC start with … “poor”

Oncotarget43016www.impactjournals.com/oncotarget

w w w .im pact journals.com / oncotarget / Oncotarget , Vol. 6 , No. 4 0

I nhibit ion of the Tcf/ beta- catenin com plex increases apoptosis

and im pairs adrenocort ical tum or cell proliferat ion and adrenal

steroidogenesis

Let ícia F. Leal1 , Ana Carolina Bueno1 , Débora C. Gom es1 ,2 , Rafael Abduch 1,

Margaret de Castro3, Sonir R. Antonini1

1Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

2Department of Pediatrics, School of Medicine, Federal University of Uberlandia, Uberlândia, Minas Gerais, Brazil

3Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

Correspondence to:

Sonir R. Antonini, e- m ail: [email protected]

Keywords: adrenoc ortic a l c anc er, beta -c a tenin, steroidogenesis, apop tosis, ta rgeted therapy

Received: April 13, 2015 Accepted: September 05, 2015 Published: Oc tober 16, 2015

ABSTRACT

Background: To date, there is no effect ive therapy for pat ients w ith advanced/

metastatic adrenocortical cancer (ACC). The activation of the Wnt/ beta-catenin

signaling is frequent in ACC and this pathw ay is a prom ising therapeut ic target .

Aim: To investigate the effects of the inhibition of the Wnt/ beta-catenin in ACC cells.

Methods: Adrenal (NCI -H295 and Y1) and non-adrenal (HeLa) cell lines were

t reated w ith PNU- 7 4 6 5 4 ( 5–2 0 0 μM) for 2 4–9 6 h to assess cell viability ( MTS-based

assay) , apoptosis (Annexin V) , expression/ localization of beta-catenin (qPCR,

immunofluo rescence, immunocytochemistry and western blot) , expression of

beta-catenin target genes (qPCR and western blot) , and adrenal steroidogenesis

( radioim m unoassay, qPCR and w estern blot ) .

Results: I n NCI - H2 9 5 cells,PNU- 7 4 6 5 4 significa nt l y decreased cell proliferat ion

96 h after treatment, increased early and late apoptosis, decreased nuclear beta-

catenin accumulation, impaired CTNNB1/ beta-catenin expression and increased beta-

catenin target genes 48 h after treatment. No effects were observed on HeLa cells.

I n NCI -H295 cells, PNU-74654 decreased cortisol, testosterone and androstenedione

secretion 24 and 48 h after treatment. Additionally, in NCI -H295 cells, PNU-74654

decreased SF1 and CYP2 1 A2 m RNA expression as w ell as the protein levels of STAR

and aldosterone synthase 48 h after treatment. I n Y1 cells, PNU-74654 impaired

cort icosterone secret ion 2 4 h after t reatm ent but did not decrease cell viability.

Conclusions: Blocking the Tcf/ beta-catenin complex inhibits the Wnt/ beta-catenin

signaling in adrenocortical tumor cells triggering increased apoptosis, decreased

cell viability and impairment of adrenal steroidogenesis. These promising find i ngs

pave the way for further experiments inhibiting the Wnt/ beta-catenin pathway in

pre-clinical models of ACC. The inhibition of this pathway may become a promising

adjuvant therapy for pat ients w ith ACC.

INTRODUCTION

The management of patients with adrenocortical

carcinomas (ACCs) remains a challenge and patients

with invasive, metastatic or recurrent disease have a poor

prognosis [1, 2]. Although significa nt progress has been

achieved in recent years both in basic and clinical research,

adjuvant therapeutic options for patients with ACC remain

very limited [3]. Mitotane (M), the firs t line adjuvant

treatment, is highly toxic and its combination with

etoposide, doxorubicin, and cisplatin (EDP) is generally

ineffective and almost all patients will experience disease


Target therapy in ACC: at best stable disease

Fassnacht et al. J Clin Endocrinol Metab 2013

• Wrong disease?

• Wrong patient setting/marker?

• Wrong drugs?


Immunotherapy

Fay et al. J Immunother Cancer 2015


Failure of immunotherapy

Tissier et al. Cancer Res 2005

Spranger et al. Nature 2015


• Up to 80% of radically operated patients relapse within 2 years

• Risk factors for relapse • Stage: I-II vs III • Radicality: R0 vs R1 • Ki67: <10% vs >10%

• This observation represents the rationale for adjuvant treatments

Risk of relapse in R0-R1 operated ACC

Berruti et al. J Clin Oncol 2012


ESMO algorythm for adjuvant strategies

• First, consider resection status (R0 vs R1-R2)

• Second, consider stage (I-II vs III) and Ki67 (<10% vs >10%)

Berruti et al. Ann Oncol 2012



ESMO algorythm for adjuvant strategies

Berruti et al. Ann Oncol 2012

• “patients with potential residual disease (R1 or Rx resection) and/or Ki67 more than 10% should be offered adjuvant mitotane”

• Caveat: No randomized trials in this setting!


Adjuvant Mitotane for operated ACC

• Retrospective analysis of two cohorts

• Median RFS 42 vs 10/25 months, p <0.001

• Median OS 110 vs 52 (p 0.01) and 67 (p 0.10) months

Terzolo et al. NEJM 2007

47 Italian pts

75 German pts

55 Italian pts


Adjuvant Mitotane for operated ACC: update 2017

Berruti et al. J Clin Endocrinol Metab 2017


What is Mitotane?

D-D-D

D-D-T


Toxicity of Mitotane

Allolio et al. J Clin Endocrinol Metab 2006


• The so called “therapeutic range” (14-20 mg/ml) is attained within 2-3 months

• Question: Is Mitotane adequate for an ACC with high proliferative activity (Ki67)?

Major drawback of adjuvant mitotane


Adjuvant chemotherapy for adrenocortical carcinoma: a multicenter randomized open label phase III trial: the ACACIA trial

Italian Agency of Medicine 2016 call

Funded !!!

Adiuvant Chemotherapy for Adrenocortical CarcInomA


Metastatic pattern of ACC

• Majority of ACC with tumor extending beyond the adrenal

• Lungs (45%)

• Liver (42%)

• Lymphnodes (24%)

• Bone, pancreas, spleen, diaphragm, peritoneum


Strategy for inoperable/metastatic ACC

• Backbone of treatment is mitotane or chemo + mitotane

+ local regional options

EDP-M for non secreting ACC

EDP-M-M for secreting ACC


EDP efficacy the FIRM-ACT trial: the first phase III trial in ACC

Fassnacht et al. NEJM 2012


The FIRM-ACT trial: >300 ACC patients randomized

Fassnacht et al. NEJM 2012

Crossover permitted at PD


The FIRM-ACT trial: results

Fassnacht et al. NEJM 366(23):2189-97; 2012

EDP-M median PFS: 5.0 months

Sz-M median PFS: 2.1 months

EDP-M median OS: 14.8 months

Sz-M median OS: 12.0 months


At 18 months pts without PD

EDP-M 16.5%

Sz-M 5.2%


What is the advantage of combining mitotane and chemo?

Chemo effect

Mitotane maintenance

Chemotherapy can obtain a disease control when mitotane levels is not in the therapeutic range

ACC highly-proliferative: chemotherapy activity predominant

ACC slowly-proliferative: mitotane activity predominant


Stesso approccio in neoadiuvante

Metabolic downstaging

Tumor volume downstaging

Ki67 60% Ki67 12%


Big successes in clinical oncology & survival @ 2 years a provocative slide

M+ cancer First author Drug/Schedule OS @ 2 yrs Journal/Year

Breast Her2+ Baselga D + Trast + Pert 80% NEJM 2012

Lung Alk+ Shaw Crizotinib 50% NEJM 2013

Adrenal Fassnacht EDP-M 30% NEJM 2012

Glioblastoma Stupp RT + TMZ 26% NEJM 2005

Melanoma Robert Ipilimumab 18% NEJM 2011

Gastric Van Cutsem DCF 18% JCO 2006

Pancreas Conroy Folfirinox 12% NEJM 2011


What is the prognosis of ACC?

Most of papers on ACC start with … “poor”

Oncotarget43016www.impactjournals.com/oncotarget

w w w .im pact journals.com / oncotarget / Oncotarget , Vol. 6 , No. 4 0

I nhibit ion of the Tcf/ beta- catenin com plex increases apoptosis

and im pairs adrenocort ical tum or cell proliferat ion and adrenal

steroidogenesis

Let ícia F. Leal1 , Ana Carolina Bueno1 , Débora C. Gom es1 ,2 , Rafael Abduch 1,

Margaret de Castro3, Sonir R. Antonini1

1Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

2Department of Pediatrics, School of Medicine, Federal University of Uberlandia, Uberlândia, Minas Gerais, Brazil

3Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil

Correspondence to:

Sonir R. Antonini, e- m ail: [email protected]

Keywords: adrenoc ortic a l c anc er, beta -c a tenin, steroidogenesis, apop tosis, ta rgeted therapy

Received: April 13, 2015 Accepted: September 05, 2015 Published: Oc tober 16, 2015

ABSTRACT

Background: To date, there is no effect ive therapy for pat ients w ith advanced/

metastatic adrenocortical cancer (ACC). The activation of the Wnt/ beta-catenin

signaling is frequent in ACC and this pathw ay is a prom ising therapeut ic target .

Aim: To investigate the effects of the inhibition of the Wnt/ beta-catenin in ACC cells.

Methods: Adrenal (NCI -H295 and Y1) and non-adrenal (HeLa) cell lines were

t reated w ith PNU- 7 4 6 5 4 ( 5–2 0 0 μM) for 2 4–9 6 h to assess cell viability ( MTS-based

assay) , apoptosis (Annexin V) , expression/ localization of beta-catenin (qPCR,

immunofluo rescence, immunocytochemistry and western blot) , expression of

beta-catenin target genes (qPCR and western blot) , and adrenal steroidogenesis

( radioim m unoassay, qPCR and w estern blot ) .

Results: I n NCI - H2 9 5 cells,PNU- 7 4 6 5 4 significa nt l y decreased cell proliferat ion

96 h after treatment, increased early and late apoptosis, decreased nuclear beta-

catenin accumulation, impaired CTNNB1/ beta-catenin expression and increased beta-

catenin target genes 48 h after treatment. No effects were observed on HeLa cells.

I n NCI -H295 cells, PNU-74654 decreased cortisol, testosterone and androstenedione

secretion 24 and 48 h after treatment. Additionally, in NCI -H295 cells, PNU-74654

decreased SF1 and CYP2 1 A2 m RNA expression as w ell as the protein levels of STAR

and aldosterone synthase 48 h after treatment. I n Y1 cells, PNU-74654 impaired

cort icosterone secret ion 2 4 h after t reatm ent but did not decrease cell viability.

Conclusions: Blocking the Tcf/ beta-catenin complex inhibits the Wnt/ beta-catenin

signaling in adrenocortical tumor cells triggering increased apoptosis, decreased

cell viability and impairment of adrenal steroidogenesis. These promising find i ngs

pave the way for further experiments inhibiting the Wnt/ beta-catenin pathway in

pre-clinical models of ACC. The inhibition of this pathway may become a promising

adjuvant therapy for pat ients w ith ACC.

INTRODUCTION

The management of patients with adrenocortical

carcinomas (ACCs) remains a challenge and patients

with invasive, metastatic or recurrent disease have a poor

prognosis [1, 2]. Although significa nt progress has been

achieved in recent years both in basic and clinical research,

adjuvant therapeutic options for patients with ACC remain

very limited [3]. Mitotane (M), the firs t line adjuvant

treatment, is highly toxic and its combination with

etoposide, doxorubicin, and cisplatin (EDP) is generally

ineffective and almost all patients will experience disease


Conclusioni

• La prognosi ATTUALE dei pazienti con ACC è severa perché:

• Intrinsecamente malattia aggressiva • È rara • È trattata in modo inadeguato dagli endocrinologi • È trattata in modo inadeguato dagli oncologi • La chirurgia deve essere dedicata

• La chirurgia R0 rimane l’elemento terapeutico decisivo

• Considerare CT neoadiuvante

• Considerare sempre l’associazione di terapia endocrina + oncologica

• Importanza dei centri di riferimento e della collaborazione internazionale


ACC epidemiology: very, very, very rare disease

• Annual incidence: (adult) 0.5-2.0 case per million people per year

(children) 0.2-0.3 case per million people per year

• Ratio Male/Female: 1 : 1.5

• Bimodal age distribution: First peak < 10 years

Second peak 4°-5° decade (mean age 45)


UNIBS


Thanks! ACC Fans Brescia Medical Oncology Alfredo Berruti Sara Cerri Deborah Cosentini Melanié Claps Andrea Crema Laura Ferrari Vittorio Ferrari Barbara Lazzari Experimental Pharmacology Silvia Beretta Sandra Sigala Internal Medicine & Endocrinology Maurizio Castellano Surgery Department Guido M. A. Tiberio Pathology Department Simona Fisogni Luigi P Poliani Fabio Facchetti

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Adrenal carcinoma and pheochromocytoma - media.aiom.itmedia.aiom.it/userfiles/files/doc/AIOM-Servizi/slide/20180302MI_51... · What is the Concern with an Adrenal Incidentaloma? Presented