Endocrine Gland Tumours

29/11/2016
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Adrenal cancer
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Salvatore Grisanti, Alfredo Berruti
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Department of Medical Oncology
ad University of Brescia - Spedali Civili di Brescia
a re Milan, 25-27 November 2016 - ESO/ESMO
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Conflict of interest
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Nothing to disclose
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a r Milan, 25-27 November 2016 - ESO/ESMO
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Outline
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1. Educational course on Adrenocortical carcinoma based on ESMO 2012
guidelines
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2. Consider these guidelines as the abstract for this presentation
(http://annonc.oxfordjournals.org/content/23/suppl_7/vii131.long)
u
new/investigational
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3. For each issue it is showed what is standard and why and what is
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Adrenal cancer
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Berruti et al. Ann Oncol 2012
Milan, 25-27 November 2016 - ESO/ESMO
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Anatomy and Physiology
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History of the adrenal gland
First described as a “gland” by Bartholomeus Eustachius in 1563
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B. Eustachius 1500 or 1514 - 1574
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https://en.wikipedia.org/wiki/Bartolomeo_Eustachi
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Histologic anatomy of the adrenal gland
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Organogenesis of the adrenal gland
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Wood and Hammer. Mol Cell Endocrinol, 2011
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Stem cells gradient in the adult adrenal gland
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• Adrenal progenitor cells reside under the capsule and migrate towards the
inner layers
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Adrenal progenitor cells
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Physiology of the adrenal gland
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Mineralcorticoid (Salt)
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Glucocorticoid (Sugar)
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Androgens (Sex)
ad Cathecholamines
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Biosynthesis of steroidal hormones
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Adrenal mass: “incidentaloma”
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• Detected in 0.5-5% of non-adrenal directed CT scans
• Detected in 2% of autoptic studies
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ad 12% ACC is a main indication for adrenalectomy1
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1Kebebew et al. World J Surg 2006
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Adrenal neoplasms
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• Metastases (most common adrenal cancer)
•
•
•
Lung
Breast
Melanoma
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• Renal Cell Carcinoma
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• Lymphoma
• Leukemia
• Pancreatic carcinoma
o
• Colo-rectal carcinoma
• Ovary carcinoma
• Adrenal Medullary Carcinoma

•
•
Pheochromocytoma
Ganglioneuroblastoma
lt s
u
• Neuroblastoma
• Neuroendocrine carcinoma
ad
• Adrenal Cortical Carcinoma (ACC)
• Miscellaneous
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• Primary adrenal lymphoma, Hamartoma, Teratoma, Myelolipoma, Angiomyolipomas, Amyloidosis, Plexiform
neurofibromas, Massive macronodular adrenal hyperplasia, Mixed tumors, …
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Adrenal neoplasms
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• Metastases (most common adrenal cancer)
•
•
•
Lung
Breast
Melanoma
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• Renal Cell Carcinoma
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• Lymphoma
• Leukemia
• Pancreatic carcinoma
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• Colo-rectal carcinoma
• Ovary carcinoma
• Adrenal Medullary Carcinoma

•
•
Pheochromocytoma
Ganglioneuroblastoma
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• Neuroblastoma
• Neuroendocrine carcinoma
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• Adrenal Cortical Carcinoma (ACC)
• Miscellaneous
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Epidemiology & Genetics
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ACC: epidemiology
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• Annual incidence:
a
(adult) 0.5-2.0 case per million people per year
c
(children) 0.2-0.3 case per million per year
• Ratio Male/Female: 1 : 1.5
l i d
• Bimodal age distribution:
- First peak < 10 years
s o
- Second peak 4°-5° decade (mean age
lt
45)
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Terzolo et al. NEJM 2007
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Pediatric ACC in Brazil
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• Incidence of ACC is 10-15 times higher in
children in southern Brazil1 compared to
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worldwide
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• Related to the high prevalence of an inherited
germline p53 mutation (R337H allele)2,3
• The R337H mutated allele is a low penetrance

allele that acts in a tissue-specific way2
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1Mc Ateer et al. J Pediatr Surg 2013; 2Ribeiro et al. PNAS 2001; 3Wasserman et al. JCO 2015;
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Sporadic vs hereditary syndromes-associated ACC
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Genetic landscape of ACC: 3 main drivers
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Juhlin et al. J Clin Endocrinol Metabol 2015
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Molecular pathogenesis of ACC: 3 main drivers
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• Wnt/beta catenin pathway
(activating mutations in >30%)
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s
(locus 11p15 overexpressed in 90%)
o
• Insulin-like Growth Factor-2 (IGF-2) pathway
• p53 pathway
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(mutations in >30%; allelic losses (LOH) in >85% )
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Is ACC a high-proliferative neoplasm?
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Stage III-IV patients
Ki67 (%)
i
(N = 226)1
o l <20
≥20
103 (46%)
123 (54%)
lt s
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1Libè et al. Ann Oncol 2015;
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What is new in molecular biology of ACC?
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• Whole genome doubling event is a marker of
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ACC progression (can represent a model for other neoplasms)
s
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ad
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Zheng et al. Cancer Cell 2016
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Pathology
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Pathology: general issues
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ESMO guidelines
“Histological diagnosis should be done by an experienced
c a
d
pathologist …”
• Weiss score
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s
• Mitotic/Proliferative parameters (Ki67)
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Pathology: Weiss score
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• Discriminates between benign vs malignant adrenal tumor
1) Nuclear grade (III or IV)
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2) Mitotic rate: >5/50 HPF (x40 objective)
3)
4)
5)
Atypical mitotic figures
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Cytoplasm: <25% clear or vacuolated cells
Diffuse architecture
o
6)
7)
8)
Necrosis
Venous invasion
Sinusoid invasion
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d u 9) Capsular invasion
• Presence of 3 or more criteria is related to malignancy
a
(specificity 96%, sensitivity 100%)
e
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Weiss et al. Am J Surg Pathol 1989
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Pathology: Weiss score is prognostic
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Faria et al. Mol and Cell Endocrinol 2012
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Pathology: Ki67
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• Ki67 is expressed only in ACC and not ACA1
• Ki67 is ≥20% in >50% of stage III-IV ACC patients2
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• Ki67 is a proliferative index and measures the percentage of dividing cells (Mib1)
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ad
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1Terzolo et al. Urology 2001; 2Libè et al. Ann Oncol 2015;
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Pathology: Ki67 is prognostic
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Beuschlein et al. J Clin Endocrinol Metab 2015;
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Clinical presentation
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Clinical presentation of ACC
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• Asymptomatic
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• General symptoms: fever, anemia, pain, weight loss, anorexia
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• Complaints referable to the mass
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• Symptoms of hormone excess (functioning ACC in 60% of cases)
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Metastatic pattern of ACC
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• Majority of ACC with tumor
extending beyond the adrenal
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• Lungs (45%)
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• Liver (42%)
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• Lymphnodes (24%)
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Bone, pancreas, spleen,
d
diaphragm, peritoneum
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Lafemina et al. J Surg Oncol 2012
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Hormone excess in ACC
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c a
Hirsutism, deepening of the voice,
breast atrophy, male pattern baldness,
clitoral hypertrophy, oligomenorrhea,
d
altered libido
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s
(Attention: CME question !)
u lt
d
Severe hypertension, hypokaliemia
a
Gynecomastia, breast tenderness,
decreased libido, testicular atrophy
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Lafemina et al. J Surg Oncol 2012
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Cushing’s syndrome in ACC
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•
c a
Secondary to corticosteroid (cortisol) excess
d
• Metabolic abnormalities:
o l i
• Glucose intolerance/Diabetes
• Osteoporosis/Fractures
• Hypertension
lt s • Immunedeficiency (lymphocytotoxic effect of

glucocorticoids)
d u • Psychiatric disorders
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Prognostic Role of Overt Hypercortisolism in Completely Operated
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a
Patient s with Adrenocortical Cancer
c
Alfredo Berruti a,*, Martin Fassnacht b,g, Harm Haak c, Tobias Elsed, Eric Baudin e,
Paola Sperone f, Matthias Kroiss g, Thomas Kerkhofs c, Andrew R. Williams d, Arianna Ardito h,
d
Sophie Leboulleux e, Marco Volante i, Timo Deutschbein g, Richards Feelders j , Cristina Ronchi g,
i
Salvatore Grisanti a, Hans Gelderblom k, Francesco Porpiglia l, Mauro Papotti i ,
l
Gary D. Hammer d, Bruno Allolio g, Massimo Terzolo h
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ad
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Berruti et al. Eur Urol 2014, 65:832-838
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Diagnosis & Staging
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Diagnosis of ACC: ESMO/ENSAT proposed workup
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ad
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ESMO guidelines. Ann Oncol 2012
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CT-PET in ACC: prognostic and predictive factor
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Conclusions: Patients with ACC and a high whole body MTG, TLG and SUVmax have a worse
prognosis and OS
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Satoh et al. Ann Surg Oncol 2015
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Staging of ACC: TNM-AJCC & ENSAT
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c a
%
l i d 2%
19%
s o 18%
u lt 61%
ad
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Prognostic role of ACC staging classification
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UICC/WHO 2004 ENSAT 2008
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l i d
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ad
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Fassnacht et al. Cancer 2009
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Treatment
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Two diseases in one
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• The clinical management of ACC is challenging because the clinician have
c a
l i d
to face two problems at the same time in most patients (>60%)
o
• The neoplastic mass & metastases
s
• The endocrinological-associated disease (Cushing, etc …)
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a r Brescia, 28-29 ottobre 2016 - V Meeting Club Surrene
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Treatment of hormonal excess
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Drug
Drugs used to manage Cushing in ACC
Initial dose Titration
c a
Maximum dose
Mitotane 1-2 g/d

il d
1-2 g every 1-2 weeks
o
6-10 g/d
s
400 mg/d every 1-2
Ketoconazole 600 mg/d 3600-6400 mg/d
days
Metyrapone
u l t
0.5–1.0 g/d
0.5-1.0 g every few
days
4-6 g/d
ad
a r e
Veytsman et al. J Clin Oncol 2009
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TreatmentDrugs used to manage
of hormonal Cushing in ACC
excess
n c
a
Drug Adverse effects
MitotaneMitotane
CYP3A4
isdisturbance,
the most toxic
inducer
skin drugrash, and
d
hypothyroidism, liver toxicity c
Nausea, vomiting, anorexia, diarrhea, confusion, ataxia, speech
is a strong
dyslipidemia, gynecomastia,
Ketoconazole
gynecomastia, important
hypertension,
o l i
Nausea, vomiting, abdominal pain, fever, weakness,
Ketoconazole may have liver toxicity and
liver toxicity
is a strong CYP3A4 inhibitor
Metyrapone
Metyrapone
lt
is the best tolerated drug
s
Hypertension, alopecia, hirsutism, acne, nausea, abdominal
u
discomfort, headache, weakness, leucopenia
ad
a r e
Veytsman et al. J Clin Oncol 2009
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Global management of ACC: standard options by stage
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Stage
c a
il d
Therapy
I II III IV
Surgery
s
Yes +/- RT
o Yes +/- RT Yes Yes
Systemic
therapy
Mitotane
u
Chemotherapy l t Yes Yes
Yes
ad
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The mass: surgery in localized ACC
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• Surgery is the mainstay of therapy and represents the only chance of cure
l i d %
o
2%
19%
lt s 18%
Curable
(39%)
d u 61%
e a
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Resection status is a major prognostic factor
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• The ideal goal of surgery is to obtain a R0 resection
c a
i d
overall survival
0,8
l
0,6 R0 resect.; n=177
o
0,4
R1 resec.; n=27
s
0,2
lt
0
0 1 2 3 4 5 6 7 8 9 10
p < 0,001
years
d u
To achieve a R0 resection it is often mandatory to resect parts of adjacent
organs such as the wall of the vena cava, liver, spleen, colon, pancreas,
a
stomach
• Nephrectomy may be avoided if the tumor is not invading the kidney
e
• Locoregional lymphadenectomy improves tumor staging and outcome
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Anatomy of the adrenal gland: key points
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c a
• Retroperitoneal organ
l i d
• Relationship with IVC (neoplastic
thrombosis is an issue)
s o • Right adrenal close to lower liver

margin; Left adrenal close to
lt
stomach and spleen
u
• Caeliac ganglion & plexus
ad • Orthosympatic afferents
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Where to perform surgery?
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• Surgical resection should be performed in centers with a high numbers of
adrenalectomy per year (al least 10/year)
c a
l i d
s o
•
u
•
months) (p <0.001)
lt
Mean time to recurrence was longer in the HVC group
(25.2 ± 28.1 months) than in the LVC (10.1 ± 7.5
Higher rate of lymphnode dissection and multiorgan
ad resection
a re
Lombardi et al. Langenbecks Arch Surg 2012
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Which surgery?
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• Two different approaches are possible for adrenalectomy:
c a
d
• Open surgery adrenalectomy (OA)
• Laparoscopic adrenalectomy (LA)
o l i
lt s
• No prospective trials are available to determine which is the best strategy
d u
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Open surgery vs laparoscopic adrenalectomy?
n c
c a
l i d
s o
u lt
ad
• Comparable recurrence-free survival in OA and LA groups
• Type of surgical treatment is not a prognostic factor
a re
Porpiglia et al. Eur Urol 2010
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n c
c
• Retrospective analysis of 267 patients from the NCI referred for recurrent
or advanced ACC a
l i d
• Extensive peritoneal dissemination: >55% vs 3% (p <0.0001) in patients
o
who have undergone laparoscopic vs open resection compared
lt s
• Conclusions: “While this has been debated in the literature, our data
argue for an end to laparoscopic resection of ACCs in order to avoid
peritoneal dissemination, a complication of laparoscopy that is uniformly
d u
fatal”.
• Take home message: (If the surgeon is not adrenal-committed) tumor
e a
rupture makes a curable ACC incurable!
r
Payabyab et al. Clin Cancer Res 2016
a
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OA vs LA: ESMO guidelines
n c
c
• Open surgery with transperitoneal access is the standard treatment of all
a
patients with localized (stage I–II) and local advanced stage (stage III) ACCs
when complete resection can be achieved.
l i d
o
• Laparoscopic adrenalectomy is a safe and effective procedure for a selected
group of patients with small ACCs (<8 cm) without preoperative evidence for
potentially malignant.
lt s
invasiveness and adrenal masses (e.g. incidentalomas) that are judged as only
d u
e a
r
ESMO guidelines. Ann Oncol 2012
a
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Risk of relapse in R0-R1 operated ACC
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• Up to 80% of radically operated patients relapse within 2 years
c a
d
• Risk factors for relapse
• Stage:
• Radicality:
• Ki67:
I-II vs III
R0 vs R1
<10% vs >10%
o l i
lt s
•
d u
This observation represents the rationale for adjuvant treatments
e a
r
Berruti et al. J Clin Oncol 2012
a
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ESMO algorythm for adjuvant strategies
n c
c a
l i d
s o
u lt
• First, consider resection status (R0 vs R1-R2)
ad • Second, consider stage (I-II vs III) and Ki67 (<10% vs >10%)
a re
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Adjuvant radiotherapy in ACC
n c
Local recurrence improved RFS not improved
c a
OS not improved
l i d
s o
u lt
ad
a re
Sabolch et al. Int J Radiat Oncol Biol Phys 2015
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Adjuvant radiotherapy in ACC
n c
• Clinical Tumor Volume (CTV) to
include the entire preoperative
gross tumor volume
c a
• Para-aortic lymph node CTV should
be contoured to include the aorta
l i d
o
with the addition of a 1 cm radial
margin into surroundings tissue
• 50 Gy to CTV if R0
• 55 Gy to CTV if R1
lt s
u
• 45 Gy to LN basin
ad
a r e
Sabolch et al. Int J Radiat Oncol Biol Phys 2015
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c a
l i d
so
ult
ad
a re
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c a
l i d
s o
u lt
ad
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c a
l i d
so
ult
ad
a re
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Adjuvant Mitotane for operated ACC
n c
c a
• Retrospective analysis of two cohorts
• Median RFS 42 vs 10/25 months, p <0.001
l i d
• Median OS 110 vs 52 (p 0.01) and 67 (p 0.10) months
s o
u
47 Italian pts
lt
ad 55 Italian pts
75 German pts
a re
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Adjuvant therapy: future scenarios
n c
•
• Validation of predictive factors in adjuvant setting

c a
Patient selection on the basis of predictive factors in addition to prognostic factors.
l i d
Mitotane alone could not be effective in rapidly proliferating tumors
o
Prospective randomized clinical trial of combination of chemo + mitotane in
s
adjuvant setting in case of rapidly proliferating ACC
u lt
ad
a r e
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What is Mitotane?
n c
a
D-D-D
d c
o l i
D-D-T
lt s
d u
e a
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Mitotane: few points to remember
n c
•
•
c a
Mitotane has adrenolytic activity (controls both cancer and hormonal excess)
Mitotane is given only as oral tablets, it is better absorbed with milk/derivatives
d
and fat-containing meals and it accumulates in adipocytic tissue
l i
Pharmacokinetic pattern is highly variable inter- and intra-individuals
o
s
• Therapeutic effect is attained within 3 months (implication: is M adequate for
ACC with high Ki67?)
u lt
Therapeutic window is narrow within plasma levels of 14-20 mg/L (Attention:
CME question !)
ad
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Mitotane plasma levels
n c
c a
l i d
Recurrence Free Survival
s o Overall Survival
u lt
ad
a re
Terzolo et al. Eur J Endocrinol 2013
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Toxicity of Mitotane
n c
c a
l i d
s o
u lt
ad
a re
Allolio et al. J Clin Endocrinol Metab 2006
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Mitotane & drug interactions
n c
c a
l i d
o
Molecular Cytotoxic agents
target agents
Substrates of CYP3A4
lt s
Axitinib
Dasatinib
Erlotinib
Gefitinib
Imatinib
Taxanes
Anthracyclines
Etoposide
Vinca alkaloids
u
Nilotinib
Lapatinib
d
Sorafenib‡
Sunitinib‡
a
Vandetanib
Everolimus
a re
Kroiss et al. Clin Endocrinol 2011
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Inoperable, recurrent and metastatic ACC
n c
c a
l i d
s o
u lt
+ local regional options
ad • Backbone of treatment is mitotane or chemo + mitotane
a re
Terzolo et al. J Endocrinol Invest 2014
Brescia, 28-29 ottobre 2016 - V Meeting Club Surrene
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EDP schedule
n c
c a
l i d
s o
u lt
ad
a re
Berruti et al. Endocr Relat Cancer 2005
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Inoperable, recurrent and metastatic ACC
n c
c a
l i d
o
EDP-M median PFS: 5.0 mo
Sz-M median PFS: 2.1 mo
lt s
d u
e a
r
Fassnacht et al. NEJM 2012
a
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n c
Median PFS (months)
c a
EDP-M
Sz-M
l i d 5.0
2.1
s o
ult
ad
a re
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n c
c a
l i d
At 18 months pts without PD
o
EDP-M 16.5%
s
Sz-M 5.2%
ult
ad
a re
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n c
c a
l i d
so
lt
Maintenance of mitotane?
d u
e a Potentially cured?
a r
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What is the prognosis of ACC?
n c
Most of papers on ACC start with … “poor”
c a
l i d
s o
u lt
ad The management of patients with adrenocortical
carcinomas (ACCs) remains a challenge and patients
with invasive, metastatic or recurrent disease have a poor
a re prognosis [1, 2]. Althoughasignificnt progress has been
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Big successes in clinical oncology & survival @ 2 years
a provocative slide
n c
M+ cancer First author Drug/Schedule OS @ 2 yrs
c
Journal/Year
a
d
Breast Her2+ Baselga D + Trast + Pert 80% NEJM 2012
Lung Alk+
Adrenal
Shaw
Fassnacht
Crizotinib
EDP-M
o l i
50%
30%
NEJM 2013
NEJM 2012
s
Glioblastoma Stupp RT + TMZ 26% NEJM 2005
Melanoma Robert Ipilimumab 18% NEJM 2011
Gastric
u
Pancreas
Van Cutsem
Conroy
ltDCF
Folfirinox
18%
12%
JCO 2006
NEJM 2011
ad
a r e Milan, 25-27 November 2016 - ESO/ESMO
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Is this the same old story?
100
n c
80
c a
60
l i d
40
s o
20
u lt
ad0
1960 1970 1980 1990 2000 2010 2020 2030 2040
a r e
Courtesy of Bob Benjamin, MDACC
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e r s
n c
Target therapy & immunotherapy in ACC c a
l i d
s o
u lt
ad
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Major molecular targets in ACC
n c
Target Rationale
c a
IGF2/IGF-R1
l i d
IGF2 over-expression from expression studies and from
hereditary Beckwith-Wiedemann syndrome
TP53
s o
Often have a p53 loss of function
lt
(MDM2/HDM2) from hereditary Li-Fraumeni syndrome
d
pathway
u
Wnt/ β Catenin signalling Often dysregulated in ACC – predominantly increased Wnt
pathway signalling
e a
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Other molecular targets
n c
Target
Angiogenesis
Rationale
c a
Adrenal gland and ACC are highly vascularized
EGFR
i d
EGFR is frequently expressed in ACC
l
ACC have endogenous high expression of MDR-1 and are
MDR-1
o
generally fairly resistant to cytotoxic chemotherapy
s
compounds
lt
CYP19 the gene encoding for the enzyme aromatase and
Estrogen Receptor (ER)
ERa are overexpressed in ACC
d u
IL13Ra2
IL13Ra2 is frequently expressed in ACC and its binding
with IL13 leads to increased transforming
growth factor-b activity
e a
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Target therapy in ACC: at best stable disease
n c
c a
l i d
s o
u
• Wrong disease?
lt
ad
• Wrong patient setting/marker?
• Wrong drugs?
a re
Fassnacht et al. J Clin Endocrinol Metab 2013
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New trial design
n c
Metastatic ACC
Treatment naive
R
A
New drug
+ mitotane
PD
c a
EDP-M
d
Eligible to mitotane N
monotherapy D
O
M
o l i PD
s
Mitotane EDP-M
lt
PD
New drug EDP-M
Metastatic ACC R
d u
Treatment naive A
Rather indolent disease N
(i.e. long DFS, D
e a
low tumor burden) O
M
Mitotane
PD
EDP-M
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Immunotherapy
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c a
l i d
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a re
Fay et al. J Immunother Cancer 2015
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Future directions
n c
• Search and validation of predictive factors of treatment efficacy
c a
• Hormone-based treatment of ACC (like in breast or prostate cancer)
• Metabolic re-programming of ACC
l i d
s o
• New drugs or combination of new and old drugs
• Immunotherapy is the newborn in ACC research
• Surgery with HIPEC
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UNIBS
e a
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ACC Fans Brescia

e r s
Thanks!
Medical Oncology
n c
a
Alfredo Berruti
Sara Cerri
Melanié Claps
Laura Ferrari
d c
Vittorio Ferrari
i
Marta Laganà
o lBarbara Lazzari
Ester Oneda
s
Experimental Pharmacology
Cristina Dalmiglio
lt
Chiara Fiorentini
Martina Fragni
u
Sandra Sigala
ad Internal Medicine & Endocrinology

Maurizio Castellano
Andrea Giustina
a re Surgical Department
Guido M. A. Tiberio
Silvia Ministrini
R 84

Endocrine Gland Tumours

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29/11/2016

ad University of Brescia - Spedali Civili di Brescia

a re Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

a re Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

• Adrenal Medullary Carcinoma

a r Milan, 25-27 November 2016 - ESO/ESMO

• Adrenal Medullary Carcinoma

a re Milan, 25-27 November 2016 - ESO/ESMO

• Ratio Male/Female: 1 : 1.5

• The R337H mutated allele is a low penetrance

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

• Presence of 3 or more criteria is related to malignancy

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

lt s • Immunedeficiency (lymphocytotoxic effect of

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Mitotane 1-2 g/d

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

a r Milan, 25-27 November 2016 - ESO/ESMO

s o • Right adrenal close to lower liver

a re Milan, 25-27 November 2016 - ESO/ESMO

Higher rate of lymphnode dissection and multiorgan

Milan, 25-27 November 2016 - ESO/ESMO

• Laparoscopic adrenalectomy (LA)

• Type of surgical treatment is not a prognostic factor

Milan, 25-27 November 2016 - ESO/ESMO

• Take home message: (If the surgeon is not adrenal-committed) tumor

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

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

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

Milan, 25-27 November 2016 - ESO/ESMO

• Validation of predictive factors in adjuvant setting

Milan, 25-27 November 2016 - ESO/ESMO

Mitotane is given only as oral tablets, it is better absorbed with milk/derivatives

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

ad • Backbone of treatment is mitotane or chemo + mitotane

Brescia, 28-29 ottobre 2016 - V Meeting Club Surrene

Brescia, 28-29 ottobre 2016 - V Meeting Club Surrene

a re prognosis [1, 2]. Althoughasignificnt progress has been

Milan, 25-27 November 2016 - ESO/ESMO

Melanoma Robert Ipilimumab 18% NEJM 2011

Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

a r Milan, 25-27 November 2016 - ESO/ESMO

Milan, 25-27 November 2016 - ESO/ESMO

• Metabolic re-programming of ACC

• Immunotherapy is the newborn in ACC research

• Surgery with HIPEC

ACC Fans Brescia