adrenal cancers - oncologypro...berruti et al esmo guidelines, ann oncol suppl 7:vii131-8, 2012...

Alfredo BerrutiUniversità degli Studi

di BresciaAzienda Ospedaliera

Spedali CiviliBrescia

Adrenal Cancers

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Disclosures

Research funding for ACC from Janssen Cilag and

Sanofi

Advisory Board HRA

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ADRENAL GLAND

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Malignant ACC

Malignant

Pheocromocytoma

Adrenal cancer

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Origin of paraganglioma

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Epidemiology

ACC PCC/PGL

Annual incidence: 0.5-2.0 case million/year 2-8 case million/year

Europe: 375-1.500 new cases/year 1.500-6.000 new cases/year

Ratio Male/Female: 1 : 1.5 1:1

Berruti et al ESMO guidelines, Ann Oncol Suppl 7:vii131-8, 2012

Fassnacht et al ESE Guidelines Eur J Endocrinol. 179(4): G1-G46, 2018

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Diagnostic work-up for adrenal cancer ESMO-ENS@T

Hormone assessment is important

Orbassano and Brescia series

Crona J et al Endocr Rev, 38(6):489-515; 2017Do not duplicate or d

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Diagnostic work-up

for adrenal cancer

(ENS@T)

Berruti A et al ESMO guidelines 2012

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PheochromocytomaAdrenocortical Carcinoma

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VHL

RET

NF1

PCC/PGLs susceptibility genes

SDHC

SDHB

PGL 1

PGL 3

PGL 4

von HIPPEL LINDAU

MEN2

NEUROFIBROMATOSIS 1

SDHx

SDHD

PGL 2SDHAF2

TMEM127 PHEOs/PGLs

SDHA sPGL

Castro-Vega et al Nature Comm 2015

Curras Freixes et al J Med Genet 2015

Up to 40% germ line mutations

Germ line and somatic

alterations in 70%Do not duplicate or d

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9 Driver genes

CTNNB1,

ZNRF3

TP53,

RB1

CDKN2A,

MEN1

DAXX,

TERT

MED12

Assié G et al. Nature Genetics 46(6): 607-12; 2014

Juhlin CC et al. J Clin Endocrinol Metabol 100(3):E493-502; 2015

Zheng S et al. Cancer Cell 29(5):723-36; 2016

ACC: genomics and pathophysiology

Wnt/beta catenin pathway

(activating mutations in >30%)

Insulin-like Growth Factor-2 (IGF-2)

pathway (overexpressed in 90%)

p53 pathway

(inactivating mutations in >30%; allelic losses(LOH) in >85% )

3 major pathways

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Surgery is the mainstay of therapy

ACC

Type: Laparotomy (preferred)

Goal: potentially cure

PCC/PGL

Type: laparoscopy

Goal:allow long-term remission, prevent

tumor growth and progression to metastatic

disease

Preparation includes alpha- blockers

followed by the addition beta-blockers

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Characterization of Malignant PCC/PGLs

• 15-17% of PCC/PGLs are malignant

5-20% PCC

15-35% PGL

• Risk of malignancy = size of primary tumor, sympatetic PGL, SDHB mutation

Metastatic spread

– Lymph nodes 80%

– Bone tissue 72%

– Liver 50%

– Lungs 50%

5 yr mortality rate: 37% (95% CI 24-51)Jimenez et al, Curr Oncol Rep, 2013

Plouin et al EJE, 2016

Hamidi et al Clin Endocrinol 2017

Crona et al Endocr Rev 2017

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ACC: prognostic parameters

Stage

Ki67

Fassnacht M et al Cancer. 115(2):243-50; 2009.

Beuschlein F et al J Clin Endocrinol Metab. 100(3):841-9; 2015Do not duplicate or d

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ACC: prognostic parameters

p < 0,001

0

0,2

0,4

0,6

0,8

1

0 1 2 3 4 5 6 7 8 9 10

years

overa

ll s

urv

ival

R0 resect.; n=177

R1 resec.; n=27Radical Surgery (R0)

Cortisol hypersecretion

Berruti A et al. Eur Urol 65(4):832-8; 2014

ACC German Registry

Crucitti F et al Surgery 119(2):161-70; 1996

Icard P et al Surgery. 112(6):972-9; 1992

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Crona J et al Endocr Rev, 38(6):489-515; 2017

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ion from author a

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Clinical Trials

Berruti et al ESMO guidelines, 2012;

Treatment for pheochromocytoma and

paraganglioma

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Eur J Endocrinol. 179(4): G1-G46, 2018

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N Engl J Med 356 (23): 2372-80, 2007

177 ACC patients

radically operated

Adjuvant

Mitotane:

45 italian

patients

Control1:

55 italian

patients

Control2:

75 German

patients

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J Clin Endocrinol Metab 102: 1358–1365, 2017

Additional 10 yr follow-up

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Fassnacht M et al, Eur J Endocrinol. 179(4): G1-G46, 2018

Adjuvant non randomized ACC studies

Progression Free Survival

Overall Survival

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Adjuvant chemotherapy for adrenocortical

carcinoma: a multicenter randomized open label

phase III trial ACACIA trial

Italian Agency of Medicine

Adiuvant Chemotherapy for Adrenocortical CarcInomA

15 italian centers involved

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Eur J Endocrinol. 179(4): G1-G46, 2018

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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

NEJM 366(23):2189-97; 2012

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Systemic therapy for Adrenocortical carcinoma:

we are still in the Dinos era

Mitotane

Mitotane + chemotherapy

EDP scheme:

Etoposide

Doxorubicin

CisplatinBob Benjamin, MDACCDo not duplica

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Inoperable, recurrent and/or metastatic ACC

Terzolo M et al J Endocrinol Invest 37 (3): 207-17 2014

+ local regional options

G = grade (Weiss score <6 or >6 or Ki67 <20% or >20%

R = resection status of the primary

A = age younger than or older than 50 years

S = hormone-related symptoms at diagnosis

mENSATstage 5-year OS rates

III 50%

IVa 2 tumor organs 15%

IVb 3 tumor organs 14%

IVc >3 tumor organs 2%

Libe R rt al Ann Oncol 26: 2119–2125, 2015

Baudin E Endocrinol Metab Clin N Am 44: 411–434, 2015

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Serum mitotane levels as a target

Hermsen et al. J Clin Endocrinol Metab 96(6):1844-51; 2011

Survival

Haak H et al 1994

Baudin E et al. 2001

Objective response

Cancer. 92(6):1385-92

Br J Cancer. 69(5):947-51.

Major drawback:

the therapeutic range is attained within 2-3 months

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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

Grisanti S. personal presentation

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Clinical Trials

Berruti et al ESMO guidelines, 2012

Treatment for pheochromocytoma and

paraganglioma

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Baudin E, personal presentation

MIBG therapy:published series

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Baudin E, personal presentation

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Baudin E, personal presentation

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Baudin E, personal presentation

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Take home messages

The management of ACC and PCC/PGL is challenging

These patients should be preferentially treated in

experienced centers adopting a multidisciplinary approach

The extreme rarity of these diseases requires multinational

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THANK-YOU

alfredio.berruti@unibs.it

Our patients and their familiesDo not duplicate or d

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