c ancer of u nknown p rimary s ite
DESCRIPTION
C ANCER OF U NKNOWN P RIMARY S ITE. N ICHOLAS P AVLIDIS, MD, PhD, FRCP (Edin). PROFESSOR OF MEDICAL ONCOLOGY MEDICAL SCHOOL, UNIVERSITY OF IOANNINA GREECE. Barcelona , June 2012. CANCER OF UNKNOWN PRIMARY ( CUP ). 1) DEFINITION EPIDEMIOLOGY BIOLOGY - PowerPoint PPT PresentationTRANSCRIPT
CCANCER OFANCER OF UUNKNOWNNKNOWN
PPRIMARYRIMARY SSITEITE
PROFESSOR OF MEDICAL ONCOLOGY MEDICAL SCHOOL, UNIVERSITY OF IOANNINA
GREECE
Barcelona , June 2012Barcelona , June 2012
NICHOLAS PAVLIDIS, MD, PhD, FRCP (Edin)
CANCER OF UNKNOWN PRIMARY CANCER OF UNKNOWN PRIMARY
( CUP )( CUP )
1)1) DEFINITION DEFINITION
2)2) EPIDEMIOLOGY EPIDEMIOLOGY
3)3) BIOLOGYBIOLOGY
4)4) PATHOLOGY PATHOLOGY
5)5) NATURAL HISTORYNATURAL HISTORY
6)6) DIAGNOSTIC APPROACHDIAGNOSTIC APPROACH
7)7) TREATMENTTREATMENT
IIS S TTHERE A HERE A DDEFINITIONEFINITION FOR FOR
CCANCER ANCER OOF F UUNKNOWN NKNOWN
PPRIMARY RIMARY O ORIGIN ?RIGIN ?
TTHE HE DDEFINITIONEFINITION
All patients presented with histologically confirmed
metastatic carcinoma in whom a complete medical history,
careful physical examination, chest x-ray, full blood count,
stool occult blood testing and urinalysis did not identify
the primary site.
InIn 1970’s1970’s
Histologically confirmed metastatic cancer
Detailed medical history
Complete physical examination (plus pelvic and rectal exam)
Chest radiography
Full blood count
Biochemistry
Urinalysis
Stool occult blood testing
Histopathology review and use of immunohistochemistry
Computed tomography of chest, abdomen and pelvis
Mammography or MRI (in certain cases).
PET – scan (in certain cases).
CCLINICALLINICAL AND AND LLABORATORYABORATORY DDATAATA RREQUIRED EQUIRED TTO O DDEFINEEFINE A A PPATIENT AS ATIENT AS
HHAVINGAVING A A CCUPUP
WWHAT IS THE HAT IS THE IINCIDENCENCIDENCE
OF OF CCANCER OF ANCER OF UUNKNOWN NKNOWN
PPRIMARY RIMARY SSITE ?ITE ?
EPIDEMIOLOGY OF CANCER OF UNKNOWN EPIDEMIOLOGY OF CANCER OF UNKNOWN PRIMARYPRIMARY
Geographical area
Source Frequency (%)
Period
USA SEER 2.3 1973-1987
Australia New South Wales Registry
4.2 1970-1990
Netherlands Eindhoven Cancer Registry
4.0 1984-1992
Finland IARC 2.5 -
Germany - 7.8 1968-1984
Russia - 3.6 -
Switzerland Local registries 2.3 1984-1993
Japan IARC 3.0 -
THE BIOLOGY OF THE BIOLOGY OF CANCER OF UNKNOWN CANCER OF UNKNOWN
PRIMARY PRIMARY
Hypothesis AHypothesis A
CUP does not undergo CUP does not undergo type 1 progressiontype 1 progression (from a (from a
premalignant lesion to malignant) premalignant lesion to malignant)
b u tb u t
Follows a Follows a type 2 progressiontype 2 progression (malignant at the onset (malignant at the onset
of the disease without forming a primary site) of the disease without forming a primary site)
Frost P et al, Cancer Bull 1989, 41, 139-141
Hypothesis BHypothesis B
CUP follows the CUP follows the parallel progression modelparallel progression model where metastases can arise early in the where metastases can arise early in the development of a malignancy …development of a malignancy …
the the linear progression modellinear progression model where where stepwise progression of accumulating stepwise progression of accumulating genetic and epigenetic alterations genetic and epigenetic alterations accompanying cancer development accompanying cancer development
I n c o n t r a s t t o
Klein C, Nature Reviews Cancer 9: 302-312, 2009
TRANSLATIONAL RESEARCH ON CUP BIOLOGY TRANSLATIONAL RESEARCH ON CUP BIOLOGY
1.1. Chromosomal InstabilityChromosomal Instability
2.2. Oncogenes – OncoproteinsOncogenes – Oncoproteins
3.3. Tumour and Metastasis Suppressor GenesTumour and Metastasis Suppressor Genes
4.4. Angiogenesis Angiogenesis
5.5. MetalloproteinasesMetalloproteinases
6.6. Hypoxia Hypoxia
7.7. Epithelial Mesenchymal Transition and StemnessEpithelial Mesenchymal Transition and Stemness
8.8. Signaling PathwaysSignaling Pathways
TRANSLATIONAL RESEARCH IN CUP
GENE/ MOLECULE F I N D I N G S CLINICAL CORRELATIONS
IHC MUTATIONS
HER-2 4-27 % - None
EGFR 12- 61 % 0 % None
c-Kit 81 % 0 % None
PDGFR 50 % 0 % None
BCL2 40 % - None
cMYC 23 % - None
Ras 23 % - None
p53 53 % 26% None
Kiss-1 3 % 2% None
Angiogenesis
CD34 56 – 59 % - Adverse prognostic factor
VEGF 20 – 83 % - Adverse prognostic factor
Matrix Metalloproteinase
MMP-2 4 % - None
MMP -9 36 % - None
TIMP-1 44 % - Adverse prognostic factor
Hypoxia
GLUT-1
HIF 1a
COX-2
25 % Adverse prognostic factor in squamous cervical CUP
-
EMT
E-Cadherin 78.8 % - • EMT phenotype was seen in 8-16% of CUP
SNAIL 61.9 % -
Vimentin 23.2 % - • Adverse prognostic factor
N-Cadherin 13.8 %
Oct-4 0%
Signaling Pathways
cMET 42% 30 % • cMET favourable prognosis
• pMAPK adverse prognosis
• Notch-3 adverse prognosis
pMARK 54% -
Notch 1-3 2-73 % -
Jagged 1 22 % -
PTEN 50 % -• p21 favourable prognosis
• pAKT or pRPS6 adverse prognosis
• pMAPK + pAKT adverse prognosis
pAKT 73 % -
pRPS6 60 % -
p21 61% -
Cyclin D1 44% -
THE THE NNATURAL ATURAL H HISTORYISTORY OF OF
CCANCER OF ANCER OF UUNKNOWN NKNOWN
PPRIMARY RIMARY S SITEITE
FUNDAMENTAL CHARACTERISTICSFUNDAMENTAL CHARACTERISTICS
Early disseminationEarly dissemination
Clinical absence of primary at presentationClinical absence of primary at presentation
Aggressiveness Aggressiveness
Unpredictable metastatic patternUnpredictable metastatic pattern
UNPREDICTABLE METASTATIC UNPREDICTABLE METASTATIC PATTERNPATTERN
Refers to the differences in the incidence of metastatic Refers to the differences in the incidence of metastatic
sites at diagnosis between known and unknown primary sites at diagnosis between known and unknown primary
carcinomascarcinomas
E x a m p l e E x a m p l e
Pancreatic cancerPancreatic cancer presenting as CUP has 4-fold higher presenting as CUP has 4-fold higher
incidence to affect bones, and 30% incidence to appear with incidence to affect bones, and 30% incidence to appear with
lung metastases.lung metastases.
CCancer of ancer of
UUnknown nknown
PPrimary Site :rimary Site :
One or moreOne or more
Diseases ?Diseases ?
H I S T O L O G YH I S T O L O G Y I N C I D E N C EI N C I D E N C E
A d e n o c a r c i n o m aA d e n o c a r c i n o m a
Well to moderately differentiated
Poorly or undifferentiated
S q u a m o u s c e l l c a r c i n o m aS q u a m o u s c e l l c a r c i n o m a
U n d i f f e r e n t i a t e d ne o p l a s m U n d i f f e r e n t i a t e d ne o p l a s m
ss
Not specified carcinoma
Neuroendocrine tumors
Lymphomas
Germ cell tumors
Melanomas
Sarcomas
Embryonal malignancies
HISTOLOGICAL CLASSIFICATIONHISTOLOGICAL CLASSIFICATION
50 %35 %
10 %
5 %
CLINICOPATHOLOGICAL ENTITIES CLINICOPATHOLOGICAL ENTITIES OF CUPOF CUP
O R G A NO R G A N H I S T O L O G YH I S T O L O G Y
Liver (mainly) and/or other organs
AdenoCa M or P diff
Lymph nodes Mediastinal – Retroperitoneal
(midline distribution)U or P diff Ca
Axillary AdenoCa W to P diff
Cervical SCC Ca
Inguinal U Ca, SCC, mixed SCC / adenoCa
W = well, M = moderately, P = poorly, U = undifferentiated
Lungs
Pulmonary metastases
Pleural effusion
AdenoCa various diff
AdenoCa M or P diff
W = well, M = moderately, P = poorly, U = undifferentiated
Peritoneal cavity
Peritoneal adenocarcinomatosis
in females
Malignant ascites of other
unknown origin
Papillary or serous adenoCa
( ± psammoma bodies )
Mucin adenoCa M or P diff
( ± signet ring cells )
Melanoma U neoplasm with melanoma features.
W = well, M = moderately, P = poorly, U = undifferentiated
Bones (solitary or multiple) AdenoCa of various diff
Brain (solitary of multiple) AdenoCa of various diff or
squamous cell Ca
Neuroendocrine tumors P diff Ca with neuroendocrine
features (mainly), low-grade
neuroendocrine Ca, small cell
anaplastic Ca
WHAT IS THE WHAT IS THE OPTIMAL OPTIMAL
INVESTIGATIONAL DIAGNOSTIC INVESTIGATIONAL DIAGNOSTIC
APPROACHAPPROACH FOR THE IDENTIFICATION FOR THE IDENTIFICATION
OF THE PRIMARY TUMOR ?OF THE PRIMARY TUMOR ?
HOW DO WE SEARCH FOR THE PRIMARY ?
By IMAGING By ENDOSCOPY By HISTOPATHOLOGY
Immunohisto-chemistry
Advanced Molecular
Technology
CT- scans MRIs
PET- scans
Mammography
Ultrasonography
Conventional
Radiology
ENT panendoscopy
Bronchoscopy
Colonoscopy
Proctoscopy
Colposcopy
By By HISTOPATHOLOGYHISTOPATHOLOGY
STEPS OF IMMUNOHISTOCHEMICAL DIAGNOSTIC APPROACH FOR CUP
Carcinoma AE 1/3 pancytokeratin
Lymphoma Common leucocyte antigen (CLA)
Melanoma S100, HMB45
Sarcoma S100, Vimentin
STEP 1 (Detects broad type of cancer)
Adenocarcinoma CK 7/20, PSA
Germ cell tumour PLAP, OCT4, AFP, HCG
Hepatocellular Carcinoma Hepar 1, canalicular
pCEA/CD10/CD13
Renal cell carcinoma RCC, CD10
Thyroid carcinoma TTF1, thyroglobulin
Neuroendocrine carcinoma Chromogranin, synaptophysin,
PGP 9.5, CD56
Squamous carcinoma CK 5/6, p63
STEP 2 (Detects subtype of carcinoma)
Prostate PSA, PAP
Lung TTF1
Breast GCDFP-15, mammaglobulin, ER
Colon CD X 2, CK 20
Pancreas/Biliary CD X 2, CK 20, CK7
Ovary ER, Ca 125, mesothelin
STEP 3 (Detects origin of an adenocarcinoma)
CCYTOKERATINS (CKS)YTOKERATINS (CKS)CCYTOKERATINS (CKS)YTOKERATINS (CKS)
Monoclonal antibodies against
cytokeratin polypeptides CK7 and CK20
CK7CK7 CK20CK20CK7CK7 CK20CK20
CK7 + CK20 + CK7 + CK20 - CK7 - CK20 + CK7 - CK20 -
Urothelial tumors
Ovarian mucinous
adenocarcinoma
Pancreatic
adenocarcinoma
Cholangiocarcinoma
Lung adenocarcinoma
Breast carcinoma
Thyroid carcinoma
Endometrial carcinoma
Cervical carcinoma
Salivary gland
carcinoma
Cholangiocarcinoma
Pancreatic carcinoma
Colorectal Carcinoma
Merkel cell carcinoma
Hepatocellular
carcinoma
Renal cell carcinoma
Prostate carcinoma
Squamous cell & small
cell lung carcinoma
Head & neck carcinoma
MOLECULAR ANALYSIS MOLECULAR ANALYSIS [Microarray Platforms][Microarray Platforms] MOLECULAR ANALYSIS MOLECULAR ANALYSIS [Microarray Platforms][Microarray Platforms]
> 80 – 90 % accuracy> 80 – 90 % accuracy
Assay Platform Tissue No. of Tumor types
Number of genes
Accuracy in known tumors (%)
Veridex RT-PCR
mRNA
FFPE 6 and ”other” 10 76
Pathwork Diagnostics
Tissue of Origin test
cDNA microarray
Frozen/
FFPE
15 1500 89
Rosetta Genomics
MiReview met
RT-PCR
miRNA
FFPE 22 48 miRNAs 86
bioTheranostics
CancerType ID
RT-PCR
mRNA
FFPE 39 (including subtypes)
92 86
Gene expression Gene expression profilingprofiling
A s s a y s
Accuracy of microRNA-based classification of Accuracy of microRNA-based classification of metastases of unknown primary.metastases of unknown primary.
A b s t r a c tA b s t r a c tWe used a microarray-based test that uses the expression of 64 microRNAs to We used a microarray-based test that uses the expression of 64 microRNAs to retrospectively evaluate tumors from CUP patients. retrospectively evaluate tumors from CUP patients.
Methods:Methods: A cohort of resected metastatic lesions from patients diagnosed with CUP was A cohort of resected metastatic lesions from patients diagnosed with CUP was studied blindly on the studied blindly on the microRNA-based testmicroRNA-based test. The cohort included . The cohort included 93 samples93 samples (from 92 (from 92 patients) with tissue adequate for the test. patients) with tissue adequate for the test.
Results:Results: The test results The test results were fully concordant with the diagnosiswere fully concordant with the diagnosis based on all the clinical based on all the clinical and pathological information available including follow-up and outcome and pathological information available including follow-up and outcome in 92%in 92% of of patients compared to ~70% agreement with the patients’ diagnosis at initial presentation, patients compared to ~70% agreement with the patients’ diagnosis at initial presentation, before additional data gathered throughout patient management. before additional data gathered throughout patient management.
Conclusions:Conclusions: In a retrospective, well studied cohort of metastases from CUP patients, a In a retrospective, well studied cohort of metastases from CUP patients, a previously developed test based on the expression profile of 64 microRNAs previously developed test based on the expression profile of 64 microRNAs allowed allowed accurate identification of tissue of origin in 92% of the casesaccurate identification of tissue of origin in 92% of the cases. This study validates the high . This study validates the high accuracy of the test on real CUP patients. accuracy of the test on real CUP patients.
Nicholas Pavlidis, George E. Pentheroudakis, et al ASCO, May 2012
By IMAGING
IMAGING STUDIES IN CUP
Imaging Study
Chest X-ray
Barium studies
CT-scans
Mammography
MRI (breast)
FDG-PET SCAN
Diagnostic Value
Prerequisite test
Useless
40% accuracy / Guidance to
biopsy
Low sensitivity
60% accuracy
43% accuracy / more sensitive
for occult H+N and Lung Ca
By ENDOSCOPY
ENDOSCOPYENDOSCOPY Should always be symptoms - or sings oriented investigational Should always be symptoms - or sings oriented investigational
proceduresprocedures
ENT panendoscopyENT panendoscopy : : in cervical node in cervical node
involvementinvolvement
BronchoscopyBronchoscopy : : in radiographic indications or in radiographic indications or
symptomssymptoms
ColonoscopyColonoscopy : : in relevant symptoms and signsin relevant symptoms and signs
ProctoscopyProctoscopy : : in inguinal node involvementin inguinal node involvement
ColposcopyColposcopy : : in inguinal node involvementin inguinal node involvement
SERUM TUMOR MARKERSSERUM TUMOR MARKERS Routine evaluation of current commonly used markers have Routine evaluation of current commonly used markers have
not been proven of any prognostic or diagnostic assistancenot been proven of any prognostic or diagnostic assistance
A non – specific multiple overexpression of the adenocarcinoma A non – specific multiple overexpression of the adenocarcinoma
markers markers (CEA, CA 125, CA 15-3, CA 19-9)(CEA, CA 125, CA 15-3, CA 19-9) has been observed in has been observed in
the majority of CUP patients.the majority of CUP patients.
Worthwhile to requestWorthwhile to request : :
PSAPSA in men with bone metastatic adenocarcinoma in men with bone metastatic adenocarcinoma
Β-Β-HCGHCG & & AFPAFP in men with an undifferentiated tumor in men with an undifferentiated tumor
AFPAFP in patients with hepatic tumors in patients with hepatic tumors CA 125CA 125 women with papillary adenocarcinoma of women with papillary adenocarcinoma of
peritoneal cavity. peritoneal cavity.
CA 15-3CA 15-3 women with adenocarcinoma involving only women with adenocarcinoma involving only axillary lymph nodes axillary lymph nodes.
HOW OFTEN CAN THE HOW OFTEN CAN THE PRIMARY TUMOR BE PRIMARY TUMOR BE
INDENTIFIEDINDENTIFIED ? ?
IDENTIFICATION OF PRIMARY SITE BY EXTENSIVE ROUTINE DIAGNOSTIC WORK - UP
The antemortem frequency of detection of primary site by imaging, endoscopy or immunohistochemistry studies remains around 30%.
Pavlidis et al, Eur J Cancer 39: 1990-2005, 2003
IDENTIFICATION OF PRIMARY SITE AT AUTOPSY FROM ALL PUBLISHED SERIES
Years of Publications : 1944 - 2000
No of Autopsies : 884
Primary Site Found : 73 % (644 / 884)
Genital system 7 %Stomach 6 %Bladder / ureter 0.01
%Breast 0.007
%Other 10
%
Lung 27 %Pancreas 24 %Liver/bile duct 8 %Kidney /adrenals 8 %Bowel 7 %
Primary Sites Identified :
IDENTIFICATION OF PRIMARY SITE BY GENETIC PROFILING (MICROARRAYS) FROM ALL PUBLISHED CUP SERIES
Years of Publications : 2005- 2007
No of Samples : > 500 (cDNA)
Biological Assignment of Primaries (Accuracy) : 50 – 87 %
Primary Sites Identified:
Liver/bile duct 8 %Kidney / adrenals 6 %Bladder / ureter 5 %Stomach 3 % Other 18 %
Breast 15 %Pancreas 12.5 %Bowel 12 %Lung 11.5 %Genital system 9 %
WHAT IS THE WHAT IS THE OPTIMAL OPTIMAL
THERAPEUTICTHERAPEUTIC APPROACH OF APPROACH OF
CANCER OF UNKNOWN PRIMARY ?CANCER OF UNKNOWN PRIMARY ?
Overall comparative results of chemotherapy in Overall comparative results of chemotherapy in CUP patients. A review of all phase II non –CUP patients. A review of all phase II non –
randomized studiesrandomized studies
Overall comparative results of chemotherapy in Overall comparative results of chemotherapy in CUP patients. A review of all phase II non –CUP patients. A review of all phase II non –
randomized studiesrandomized studies
5-FU / Anthracycline combinations
Platinum based combinations
Platinum / taxane –based combinations
No articles 12 28 18
Years 1964 - 1993 1983 - 2009 1997 - 2010
No patients 738 1238 1317
Response Rate % (mean ) 16.8 33.5 39.5
Mean Survival
(months) 6.7 8.4 11.4
DO WE HAVE DO WE HAVE EFFECTIVE DRUGSEFFECTIVE DRUGS FOR CANCER OF UNKNOWN FOR CANCER OF UNKNOWN
PRIMARYPRIMARY
OR OR
WE JUST HAVE WE JUST HAVE RESPONSIVE RESPONSIVE SUBSETSSUBSETS OF PATIENTS ? OF PATIENTS ?
DIAGNOSTIC AND THERAPEUTIC
MANAGEMENT OF CANCER OF AN
UNKNOWN PRIMARY
N. Pavlidis, E. Briasoulis, J.
Hainsworth, E.A. Greco
39 : 1990 – 2
005, 2003
WHAT IS CANCER OF UNKNOWN WHAT IS CANCER OF UNKNOWN PRIMARY ? PRIMARY ?
WHAT IS CANCER OF UNKNOWN WHAT IS CANCER OF UNKNOWN PRIMARY ? PRIMARY ?
Lung-hidden CUP Pancreas-hidden
CUP
Liver-hidden CUP
Prostate-hidden CUP
Breast-hidden CUP
Colon-hidden CUP
Kidney-hidden CUP
Gastric-hidden CUP
FAVOURABLE OR GOOD PROGNOSIS SUBSETS
UNFAVOURABLE OR POOR PROGNOSIS SUBSETS
CUPCUP
THE FAVOURABLE SUBSETS THE FAVOURABLE SUBSETS
OR OR
GOOD PROGNOSIS SUBSETSGOOD PROGNOSIS SUBSETS
THE FAVOURABLE SUBSETS THE FAVOURABLE SUBSETS
OR OR
GOOD PROGNOSIS SUBSETSGOOD PROGNOSIS SUBSETS
1. Poorly differentiated carcinoma with midline distribution (extragonadal germ cell syndrome).
F a v o u r a b l e S u b s e t sF a v o u r a b l e S u b s e t s
2. Women with papillary adenocarcinoma of peritoneal cavity.
3. Women with adenocarcinoma involving only axillary lymph nodes.
4. Squamous cell carcinoma involving cervical lymph nodes
5. Poorly differentiated neuroendocrine carcinomas.
6. Men with blastic bone metastases and elevated PSA (adenocarcinoma).
8. Isolated inguinal adenopathy (squamous carcinoma).
9. Patients with a single, small, potentially resectable tumor.
7. Adenocarcinoma with a colon-profile (CK 20+, CK 7-, CDX 2+)
Pavlidis N & Pentheroudakis G. The Lancet 379 :
1428-35, 2012
CHARACTERISTICS OF PATIENTS WITH POORLY CHARACTERISTICS OF PATIENTS WITH POORLY DIFFERENTIATED CUPDIFFERENTIATED CUP
GENDER / AGEGENDER / AGE : Men / < 50 yrs: Men / < 50 yrs
TUMOR INVOLVEMENTTUMOR INVOLVEMENT : Mediastinum : Mediastinum
Retroperitoneum Retroperitoneum
LungsLungs
Lymph nodesLymph nodes
TUMOR MARKERSTUMOR MARKERS : Elevated serum levels of : Elevated serum levels of ββ-HGC or AFP-HGC or AFP
CLINICAL EVOLUTIONCLINICAL EVOLUTION : Rapid tumor growth: Rapid tumor growth
RESPONSE TO RxRESPONSE TO Rx : Favourable response to Cisplatin - based : Favourable response to Cisplatin - based chemotherapy. chemotherapy. RR 50% (CRs: 15-25%)RR 50% (CRs: 15-25%)
SURVIVALSURVIVAL : : Median : 13 monthsMedian : 13 months
15% long – term survivors15% long – term survivors
N : 64 patients
ORR (to platinum ) : 48% (CRs : 11%)
Survival : 12 mos
2-yr Survival : 18%
Cancer of Unknown Primary Patients with Midline Nodal Distribution: midway between poor and favourable
prognosis ?
Pentheroudakis G, Stoyianni A, Pavlidis N.
Cancer Treatment Reviews , 37 (2) 120-
6, 2011
Literature Review = N 714 pts, ORR : 35 – 65 % ,
Survival (median) : 12 mos
PERITONEAL CARCINOMATOSIS IN PERITONEAL CARCINOMATOSIS IN FEMALESFEMALES
PERITONEAL CARCINOMATOSIS IN PERITONEAL CARCINOMATOSIS IN FEMALESFEMALES
Incidence 10 % of invasive serous ovarian Ca, 10% of CUP patients
Mean Age ( yrs ) 60 ( 25 – 80 )
Clinical Picture Abdominal distension, pelvic masses, ascites
T H E N A T U R A L H I S T O R YT H E N A T U R A L H I S T O R Y
Surgical Picture Abdominal masses, peritoneal disease, ascites, with normal ovaries
Histology Papillary serous carcinoma ( ± psammoma bodies )
Serum CA-125 Often abnormal or markedly elevated.
WOMEN WITH PAPILLARY ADENOCARCINOMA WOMEN WITH PAPILLARY ADENOCARCINOMA
OF PERITONEAL CAVILY OF PERITONEAL CAVILY ( Peritoneal Adenocarcinomatosis )( Peritoneal Adenocarcinomatosis )
WOMEN WITH PAPILLARY ADENOCARCINOMA WOMEN WITH PAPILLARY ADENOCARCINOMA
OF PERITONEAL CAVILY OF PERITONEAL CAVILY ( Peritoneal Adenocarcinomatosis )( Peritoneal Adenocarcinomatosis )
Treatment : • As FIGO III ovarian cancer.
• Surgical cytoreduction.
• Platinum – based chemotherapy.
Response Rate : 40 – 60 % (CR : 30 %)
Survival : Median : 16 months
Long – term survival : 5-yr: 10 %
Serous Papillary Peritoneal Carcinoma: Unknown primary tumour, ovarian cancer
counterpart or a distinct entity? A systematic review
Years : 1980 – 2008 (25 studies)
No Pts : SPPCs 579
SOCs 1408
SPPCs SOCs
ORR 71% 70%
OS (median) 24,4 mos 29 mos
SPPC = Serous Papillary Peritoneal Carcinoma SOC = Serous Ovarian Carcinoma
G. Pentheroudakis, N. Pavlidis
Crit Rev Oncol Hematol 75: 27-42, 2010
ISOLATED AXILLARY NODAL METASTASES ISOLATED AXILLARY NODAL METASTASES
FROM AN OCCULT PRIMARY BREAST FROM AN OCCULT PRIMARY BREAST
CANCERCANCER
ISOLATED AXILLARY NODAL METASTASES ISOLATED AXILLARY NODAL METASTASES
FROM AN OCCULT PRIMARY BREAST FROM AN OCCULT PRIMARY BREAST
CANCERCANCER
Years : 1975 – 2006 (24 studies)
N : 689 patients
Mean Age : 52 yr
Menopause status : Postmenopausal 66%
Premenopausal 34%
Histology : Ductal adenocarcinoma 83%,
ER/PR 40 - 50/%,
HER2 31%
Nodal status : N1 : 48% > N1 : 52%
Simultaneous distant mets : 2%
Treatment and Outcome
Mastectomy / axillary dissection : 59 %
Primary breast irradiation : 26 %
Observation : 15 %
Logoregional recurrence rate : 25 % (mostly in
observation cases)
5-yr Survival : 72 % (similar to stage II-
III breast
cancer)
No survival difference between conservative management
(breast preservation + RT) and mastectomy
TREATMENT RECOMMENDATIONSTREATMENT RECOMMENDATIONS TREATMENT RECOMMENDATIONSTREATMENT RECOMMENDATIONS
AXILLARY LYMPH NODE
S u r g i c a l B i o p s y
Other Neoplasm Compatible with Breast Cancer
+ve for Breast Cancer
Complete Axillary Dissection ± BC Surgery + Radiotherapy
Standard treatment
-ve for Breast Cancer
Chemotherapy or hormonotherapy depending on age and menopausal status
Mammogram U/S MRI
Type III level of evidence Type III level of evidence
SQUAMOUS CELL CANCER INVOLVING SQUAMOUS CELL CANCER INVOLVING CERVICAL LYMPH NODESCERVICAL LYMPH NODES
Survival : • 5-year survival 35–50%.
• Documented long term disease – free survivors.
Treatment : • As locally advanced head-neck cancer.
• Surgery alone is inferior except pN1 neck disease with no
extracapsular extension.
• Radiation : both sides of neck and mucosa (entire pharyngeal
axis and larynx).
• Chemotherapy remains undefined (despite encouraging results
with Platinum-based).
POORLY DIFFERENTIATED POORLY DIFFERENTIATED NEUROENDOCRINE CARCINOMASNEUROENDOCRINE CARCINOMAS
S u r v i v a l : Median : 14.5 months
3-yr : 24%
T r e a t m e n t : Platinum – based or
paclitaxel / carboplatin – based
chemotherapy
R e s p o n s e : 50 – 70% ( CR : 25% )
Data : 1988 – 2010
No pts : 515 [Low grade = 231 (45%)]
Chemotherapy (Platinum based) : 65%
Response rate : 50-60% (CR: 20 - 30%)
Median survival : 15.5 months (11.6 – 40)
N : 15
Ioannina University Hospital Experience
Metastases
Liver only : 47 %Histology
Poorly – differentiated : 71.5 %
Well – differentiated : 28.5 %
OctreoscanPositive : 40 % Negative : 60 %
Treatment 1st linePlatinum - based 67 %Somatostatin analogs 20 %Other 13 %
PS 0-1 : 73 %
SurvivalMedian 18 months 1-year 54.5 %Poorly – differ. 15 months Well - differ. 24 months
OTHER FAVOURABLE CUP SUBSETSOTHER FAVOURABLE CUP SUBSETS
Men with adenocarcinoma blastic bone metastases (and elevated PSA)
Rx = Treat as metastatic prostate cancer
Isolated inguinal lymphadenopathy from squamous cell carcinoma
Rx = Dissection ± radiotherapy
Single metastatic site
Rx = Dissection ± radiotherapy
THE UNFAVOURABLE THE UNFAVOURABLE
SUBSETS SUBSETS OR OR
POOR PROGNOSIS POOR PROGNOSIS
SUBSETS SUBSETS
THE UNFAVOURABLE THE UNFAVOURABLE
SUBSETS SUBSETS OR OR
POOR PROGNOSIS POOR PROGNOSIS
SUBSETS SUBSETS
U N F A V O U R A B L E S U B S E T SU N F A V O U R A B L E S U B S E T S
1. Adenocarcinoma metastatic to the liver or other organs
2. Non-papillary malignant ascites (adenocarcinoma)
3. Multiple cerebral metastases (adeno or squamous Ca)
4. Multiple lung/pleural metastases (adenocarcinoma)
5. Multiple metastatic bone disease (adenocarcinoma)
6. Squamous – cell carcinoma of the abdominal cavity
Pavlidis N & Pentheroudakis G. The Lancet 379 :
1428-35, 2012
Greco F, Pavlidis N. Semin Oncol, 2009
THE SUBSET OF THE SUBSET OF ADENOCARCINOMA ADENOCARCINOMA
METASTATIC TO THE LIVER METASTATIC TO THE LIVER
THE SUBSET OF THE SUBSET OF ADENOCARCINOMA ADENOCARCINOMA
METASTATIC TO THE LIVER METASTATIC TO THE LIVER
HISTOLOGIC SPECTRUM OF LIVER METASTASES
Histology Mousseau et al
[Bull Cancer 1991]
Ayoub et al
[JCO 1998]
Hogan et al
[Clin Radiol 2002]
Poussel et al
[Gastr Clin Biol 2005]
Lazaridis et al
[Cancer Treat Rev 2008]
Total
(N= 91) (N=365) (N=88) (N=118) (N=49) (N=711)
Adenocarcinoma 78% 61% 79.5% 58% 69% 69%
Undifferentiated 12% 27% 3.5% 20% 24% 20%
Neuroendocrine - 9% 9% 14% 6% 9%
Squamous 6% 2% 4.5% 4% 0% 4%
Others 4% 1% 3.5% 4% - 3%
OVERALL RESULTS OF CHEMOTHERAPY IN OVERALL RESULTS OF CHEMOTHERAPY IN CUP PATIENTS WITH LIVER METASTASESCUP PATIENTS WITH LIVER METASTASES
OVERALL RESULTS OF CHEMOTHERAPY IN OVERALL RESULTS OF CHEMOTHERAPY IN CUP PATIENTS WITH LIVER METASTASESCUP PATIENTS WITH LIVER METASTASES
No of trials : 5 (1991, 1998, 2002, 2005, 2008)
No of patients : 711Response rate : < 20%Median survival : 5.5 months
Bull Cancer 1991, J Clin Oncol 1998, Clin Radiol 2002, Gastroent Clin Biol 2005, Cancer Treat Rev 2008
DDO WE O WE HHAVE ANY AVE ANY EEDIVENCE THAT DIVENCE THAT
TTARGETED ARGETED TTREATMENT IS REATMENT IS DDRASTIC RASTIC
IN IN CCUP UP PPATIENTS ? ATIENTS ?
No Patients : No Patients : 4747 (previously treated or poor-prognosis) (previously treated or poor-prognosis)
Treatment : Treatment : BevacizumabBevacizumab 10 mg/kg q 2wks 10 mg/kg q 2wks
ErlotinibErlotinib 150 mg p.o. daily 150 mg p.o. daily
Results Results : : 10% PR10% PR
61% SD61% SD
Survival : Median 7.4 mosSurvival : Median 7.4 mos
1-year 33%1-year 33%
J Clin Oncol 2007 May 1;25(13):1747-52
Oncologist 2009, 14(12): 1189-97
No Patients : No Patients : 6060
Regimen : Regimen : Carboplatin Carboplatin / / paclitaxel paclitaxel // Bevacizumab Bevacizumab / / ErlotinibErlotinib As first-line and maintenance (Bev/ErlotAs first-line and maintenance (Bev/Erlot))
Treatment : Treatment : 49 pts completed 4 cycles 49 pts completed 4 cycles 44 pts continued maintenance bevacizumab/erlotinib44 pts continued maintenance bevacizumab/erlotinib
Results Results : : 53% major responses53% major responses 41% stable disease41% stable disease PFS - median : 8 mosPFS - median : 8 mos 1-year : 38%1-year : 38% Survival – median: 12.6 mosSurvival – median: 12.6 mos
2-year : 27%2-year : 27%
DOES THE IDENTIFICATION OF DOES THE IDENTIFICATION OF
PRIMARY SITE BY MOLECULAR PRIMARY SITE BY MOLECULAR
PROFILING PROFILING IMPROVEIMPROVE PATIENTS’ PATIENTS’
OUTCOME ?OUTCOME ?
DOES THE IDENTIFICATION OF DOES THE IDENTIFICATION OF
PRIMARY SITE BY MOLECULAR PRIMARY SITE BY MOLECULAR
PROFILING PROFILING IMPROVEIMPROVE PATIENTS’ PATIENTS’
OUTCOME ?OUTCOME ?
??WHAT IS THE EVIDENCE TODAY ?WHAT IS THE EVIDENCE TODAY ?WHAT IS THE EVIDENCE TODAY ?WHAT IS THE EVIDENCE TODAY ?
Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site (CUP): Results of a prospective Sarah
Cannon Research Institute Trial
F. Anthony Greco, MDF. Anthony Greco, MD1,21,2; Mark S. Rubin, MD; Mark S. Rubin, MD1,31,3; David R. Spigel, MD; David R. Spigel, MD1,21,2; Samuel ; Samuel RabyRaby11; Thabiso Chirwa; Thabiso Chirwa11; Raven Quinn, MS; Raven Quinn, MS11; Catherine A. Schnabel, Ph.D.; Catherine A. Schnabel, Ph.D.44; Mark G. ; Mark G.
Erlander, Ph.D.Erlander, Ph.D.44; John D. Hainsworth, MD; John D. Hainsworth, MD1,21,2
11Sarah Cannon Research Institute (SCRI), Nashville, TN ; Sarah Cannon Research Institute (SCRI), Nashville, TN ; 22Tennessee Oncology, PLLC, Nashville, Tennessee Oncology, PLLC, Nashville, TN; TN; 33Florida Cancer Specialists/SCRI, Ft Myers, FL; Florida Cancer Specialists/SCRI, Ft Myers, FL; 44bioTheranostics, Inc., San Diego, CAbioTheranostics, Inc., San Diego, CA
Patient Flow Diagram
PRESENTED BY: F. Anthony Greco, MD
Patients enrolledN = 289
Insufficient tissue for assayN = 37
Off study
Successful assay N = 252
Not a treatment candidate N = 29
Off study
Candidate for treatment N = 223
Received empiric CUP therapyN =29
Received site-specific therapy directed by assay resultsN = 194
Received site-specific therapy for more responsive tumor types
N = 115
Received site-specific therapy for less responsive tumor types
N = 79
SITE SPECIFIC TREATMENTSSITE SPECIFIC TREATMENTS
PRESENTED BY: F. Anthony Greco, MD
Predicted Tissue of Origin Treatment
Breast Taxane/bevacizumab
ColorectalFOLFOX (or variant) + bevacizumab, or FOLFIRI (or variant) + bevacizumab
Lung cancer, non-small cell Platinum-based doublet + bevacizumab
Ovary Paclitaxel/carboplatin + bevacizumab
Pancreas Gemcitabine/erlotinib
Prostate Androgen ablation therapy
Renal Sunitinib or bevacizumab ± interferon
Other diagnoses Standard first-line treatment per guidelines
TISSUE OF ORIGIN PREDICTED BY MOLECULAR ASSAY (N = 252)TISSUE OF ORIGIN PREDICTED BY MOLECULAR ASSAY (N = 252)P
RE
SE
NT
ED
BY
: F. A
nth
on
y G
reco
, MD
Predicted Tissue of Origin Number of Patients (%)
Biliary tract (gallbladder, bile ducts)
52 (21%)
Urothelium 31 (12%)Colorectum 28 (11%)Non-Small-Cell lung 27 (11%)Pancreas 12 (5%)Breast 12 (5%)Ovary 11 (4%)Gastroesophageal 10 (4%)Kidney 9 (4%)Liver 8 (3%)Sarcoma 6 (2%)Cervix 6 (2%)Neuroendocrine 5 (2%)Prostate 4 (2%)Germ Cell 4 (2%)Skin-squamous 4 (2%)
Others 18 (10%)No prediction possible (unclassifiable)
5 (2%)
SURVIVAL IN 223 TREATED PTS AND IN SUBSETSSURVIVAL IN 223 TREATED PTS AND IN SUBSETS
PRESENTED BY: F. Anthony Greco, MD
Patient Group Number
Median survival (mo.)
All treated 223 10.8
Assay - directed treatment 194 12.5, p=0.02 Empiric treatment 29 4.7
Tumor type*Treatment responsive 115 13.4, p=0.04Less treatment responsive
79 7.6
Individual tumor typesBiliary tract 45 6.8Pancreas 12 8.2Colorectal 26 12.5NSCLC 23 15.9Ovary 10 29.6Breast 10 NYR (>24)NYR = not yet reached; *Includes 194 patients who received assay-
directed treatment
OVERALL SURVIVAL : Assay-directed treatment OVERALL SURVIVAL : Assay-directed treatment vs. empiric treatmentvs. empiric treatment
PRESENTED BY: F. Anthony Greco, MD
Time (months) Empiric Treatment Assay-directed treatment
Median Survival (mo)Assay-directed (N=194) 12.5Empiric (N=29) 4.7
p = 0.02
Ongoing Clinical Trials on CUP Ongoing Clinical Trials on CUP
Trial Phase Regimens Country
CUP-ONE II Epi / Cis / Capec ± Vandetanib UK
GEFCAPI 04 III Cis / Gemc vs standard chemo based on molecular diagnosis of the primary
France
STEPS IN DIAGNOSTIC AND THERAPEUTIC MANAGEMENT STEPS IN DIAGNOSTIC AND THERAPEUTIC MANAGEMENT
STEP I
SEARCH FOR PRIMARY SITESEARCH FOR PRIMARY SITE
Clinical, immunohistochemistry, imaging, endoscopy studies
STEP II
RULE-OUT POTENTIALLY TREATABLE OR RULE-OUT POTENTIALLY TREATABLE OR CURABLE TUMORSCURABLE TUMORS (Immunohistochemistry or other studies)(Immunohistochemistry or other studies)
i.e. Breast Cancer, Germ-cell Tumors, Lymphomas
STEP III CHARACTERIZE THE SPECIFIC CLINICOPACHARACTERIZE THE SPECIFIC CLINICOPATHOLOGICAL ENTITYTHOLOGICAL ENTITY
TREAT THE PATIENTTREAT THE PATIENT
FAVOURABLE SUBSETS
[Similarly to relevant primaries with “Curative Intent” ]
UNFAVOURABLE SUBSETS
[ With empirical chemotherapy with “Palliative Intent” or with specific Rx following gene profiling]
DIAGNOSIS OF METASTATIC CARCINOMA (by histopathology)DIAGNOSIS OF METASTATIC CARCINOMA (by histopathology)
89
THE IOANNINA CUP TEAM
Thank you Thank you