Download an unfavourble cup subset

CANCER OF UNKNOWN
PRIMARY SITE
NICHOLAS PAVLIDIS, MD, PhD, FRCP
(Edin)
PROFESSOR OF MEDICAL ONCOLOGY
MEDICAL SCHOOL, UNIVERSITY OF IOANNINA
GREECE
Barcelona , June 2012
CANCER OF UNKNOWN PRIMARY
( CUP )
1) DEFINITION
2)
EPIDEMIOLOGY
3)
BIOLOGY
4)
PATHOLOGY
5)
NATURAL HISTORY
6)
DIAGNOSTIC APPROACH
7)
TREATMENT
IS THERE
A
DEFINITION
FOR
CANCER OF UNKNOWN
PRIMARY ORIGIN ?
THE DEFINITION
In 1970’s
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.
CLINICAL AND LABORATORY DATA
REQUIRED TO DEFINE A PATIENT AS HAVING
A CUP












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).
WHAT IS THE INCIDENCE
OF CANCER OF UNKNOWN
PRIMARY SITE ?
EPIDEMIOLOGY OF CANCER OF UNKNOWN
PRIMARY
Geographical area
Source
Frequency (%)
Period
SEER
2.3
1973-1987
Australia
New South Wales
Registry
4.2
1970-1990
Netherlands
Eindhoven
Cancer Registry
4.0
1984-1992
IARC
2.5
-
Germany
-
7.8
1968-1984
Russia
-
3.6
-
Local registries
2.3
1984-1993
IARC
3.0
-
USA
Finland
Switzerland
Japan
THE BIOLOGY OF CANCER
OF UNKNOWN PRIMARY
Hypothesis A
CUP does not undergo type 1 progression (from a
premalignant lesion to malignant)
but
Follows a type 2 progression (malignant at the onset
of the disease without forming a primary site)
Frost P et al, Cancer Bull 1989, 41, 139-141
Hypothesis B
CUP follows the parallel progression model
where metastases can arise early in the
development of a malignancy …
I n
c o n t r a s t
to
the linear progression model where
stepwise progression of accumulating
genetic and epigenetic alterations
accompanying cancer development
Klein C, Nature Reviews Cancer 9: 302-312, 2009
TRANSLATIONAL RESEARCH ON CUP BIOLOGY
1.
Chromosomal Instability
2.
Oncogenes – Oncoproteins
3.
Tumour and Metastasis Suppressor Genes
4.
Angiogenesis
5.
Metalloproteinases
6.
Hypoxia
7.
Epithelial Mesenchymal Transition and Stemness
8.
Signaling Pathways
TRANSLATIONAL RESEARCH IN CUP
GENE/ MOLECULE
FINDINGS
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
25 %
-
Adverse prognostic factor
in squamous cervical CUP
COX-2
EMT
E-Cadherin
78.8 %
-
SNAIL
61.9 %
-
Vimentin
23.2 %
-
N-Cadherin
13.8 %
Oct-4
0%
• EMT phenotype was seen in 816% of CUP
• Adverse prognostic factor
Signaling Pathways
cMET
42%
30 %
•  cMET favourable prognosis
pMARK
54%
-
•  pMAPK adverse prognosis
Notch 1-3
2-73 %
-
Jagged 1
22 %
-
PTEN
50 %
-
pAKT
73 %
-
pRPS6
60 %
-
•  pAKT or pRPS6 adverse prognosis
p21
61%
-
• pMAPK + pAKT adverse prognosis
Cyclin D1
44%
-
•  Notch-3 adverse prognosis
•  p21 favourable prognosis
NATURAL HISTORY OF
CANCER OF UNKNOWN
PRIMARY SITE
THE
FUNDAMENTAL CHARACTERISTICS
 Early dissemination
 Clinical absence of primary at presentation
 Aggressiveness
 Unpredictable metastatic pattern
UNPREDICTABLE METASTATIC
PATTERN

Refers to the differences in the incidence of metastatic
sites at diagnosis between known and unknown primary
carcinomas
Example

Pancreatic cancer presenting as CUP has 4-fold higher
incidence to affect bones, and 30% incidence to appear with
lung metastases.
Cancer of
Unknown
Primary Site :
One or more
Diseases ?
HISTOLOGICAL CLASSIFICATION
INCIDENCE
HISTOLOGY
Adenocarcinoma
Well to moderately differentiated
Poorly or undifferentiated
Squamous
cell
carcinoma
Undifferentiated
Not specified carcinoma
Neuroendocrine tumors
Lymphomas
Germ cell tumors
Melanomas
Sarcomas
Embryonal malignancies
ne o p l a s m s
50 %
35 %
10 %
5%
CLINICOPATHOLOGICAL ENTITIES
OF CUP
O R GAN
HI STOLOGY
Liver (mainly)
AdenoCa M or P diff
and/or other organs
Lymph
nodes
Mediastinal – Retroperitoneal
(midline distribution)
U or P diff Ca
AdenoCa W to P diff
Axillary
Cervical
SCC Ca
Inguinal
U Ca, SCC, mixed SCC / adenoCa
W = well,
M = moderately, P = poorly,
U = undifferentiated
Peritoneal
cavity
Peritoneal adenocarcinomatosis
Papillary or serous adenoCa
in females
( ± psammoma bodies )
Malignant ascites of other
Mucin adenoCa M or P diff
unknown origin
( ± signet ring cells )
Lungs
AdenoCa various diff
Pulmonary metastases
AdenoCa M or P diff
Pleural effusion
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
Melanoma
W = well,
U neoplasm with melanoma features.
M = moderately,
P = poorly,
U = undifferentiated
WHAT IS THE OPTIMAL
INVESTIGATIONAL DIAGNOSTIC
APPROACH FOR THE IDENTIFICATION
OF THE PRIMARY TUMOR ?
HOW DO WE SEARCH FOR
THE PRIMARY ?
By
HISTOPATHOLOGY
Immunohistochemistry
By
IMAGING
Conventional
Radiology
By ENDOSCOPY
PET- scans
Advanced
Molecular
Technology
ENT
panendoscopy
Bronchoscopy
Mammography
Ultrasonography
Colonoscopy
Proctoscopy
CT- scans
MRIs
Colposcopy
By
HISTOPATHOLOGY
STEPS OF IMMUNOHISTOCHEMICAL
DIAGNOSTIC APPROACH FOR CUP
STEP 1 (Detects broad type of cancer)
Carcinoma
Lymphoma
Melanoma
Sarcoma
AE 1/3 pancytokeratin
Common leucocyte antigen (CLA)
S100, HMB45
S100, Vimentin
STEP 2 (Detects subtype of carcinoma)
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 3 (Detects origin of an adenocarcinoma)
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
CYTOKERATINS
(CKS)
Monoclonal antibodies against
cytokeratin polypeptides CK7 and CK20
CK7
CK7 + CK20 +
CK7 + CK20 -
CK20
CK7 - CK20 +
CK7 - CK20 -
Urothelial tumors
Lung adenocarcinoma
Colorectal Carcinoma
Hepatocellular carcinoma
Ovarian mucinous
adenocarcinoma
Breast carcinoma
Merkel cell carcinoma
Renal cell carcinoma
Pancreatic
adenocarcinoma
Cholangiocarcinoma
Thyroid carcinoma
Prostate carcinoma
Endometrial carcinoma
Squamous cell & small
cell lung carcinoma
Cervical carcinoma
Salivary gland
carcinoma
Cholangiocarcinoma
Pancreatic carcinoma
Head & neck carcinoma
MOLECULAR ANALYSIS
[Microarray Platforms]
> 80 – 90 % accuracy
Gene expression profiling
Assays
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
Accuracy of microRNA-based classification of metastases of
unknown primary.
Nicholas Pavlidis, George E. Pentheroudakis, et al
ASCO, May 2012
Abstract
We used a microarray-based test that uses the expression of 64 microRNAs to
retrospectively evaluate tumors from CUP patients.
Methods: A cohort of resected metastatic lesions from patients diagnosed with CUP was
studied blindly on the microRNA-based test. The cohort included 93 samples (from 92
patients) with tissue adequate for the test.
Results: The test results were fully concordant with the diagnosis based on all the clinical
and pathological information available including follow-up and outcome in 92% of
patients compared to ~70% agreement with the patients’ diagnosis at initial presentation,
before additional data gathered throughout patient management.
Conclusions: In a retrospective, well studied cohort of metastases from CUP patients, a
previously developed test based on the expression profile of 64 microRNAs allowed
accurate identification of tissue of origin in 92% of the cases. This study validates the high
accuracy of the test on real CUP patients.
By IMAGING
IMAGING STUDIES IN CUP
Imaging Study
Diagnostic Value
Chest X-ray
Prerequisite test
Barium studies
Useless
CT-scans
40% accuracy / Guidance to biopsy
Mammography
Low sensitivity
MRI (breast)
60% accuracy
FDG-PET SCAN
43% accuracy / more sensitive for
occult H+N and Lung Ca
By ENDOSCOPY
ENDOSCOPY

Should always be symptoms - or sings oriented investigational
procedures
 ENT panendoscopy
: in cervical node involvement
 Bronchoscopy
: in radiographic indications or symptoms
 Colonoscopy
: in relevant symptoms and signs
 Proctoscopy
: in inguinal node involvement
 Colposcopy
: in inguinal node involvement
SERUM TUMOR MARKERS
 Routine evaluation of current commonly used markers have
not been proven of any prognostic or diagnostic assistance
 A non – specific multiple overexpression of the adenocarcinoma
markers (CEA, CA 125, CA 15-3, CA 19-9) has been observed in
the majority of CUP patients.
 Worthwhile to request :
PSA
Β-HCG & AFP
AFP
in men with bone metastatic adenocarcinoma
in men with an undifferentiated tumor
in patients with hepatic tumors
CA 125
women with papillary adenocarcinoma of
peritoneal cavity.
CA 15-3
women with adenocarcinoma involving only
axillary lymph nodes.
HOW OFTEN CAN THE PRIMARY
TUMOR BE INDENTIFIED ?
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
No of Autopsies
: 1944 - 2000
: 884
Primary Site Found
: 73 %
Primary Sites Identified :
Lung
27 %
Pancreas
24 %
Liver/bile duct
8%
Kidney /adrenals 8 %
Bowel
7%
Genital system
7%
Stomach
6%
Bladder / ureter 0.01 %
Breast
0.007 %
Other
10 %
(644 / 884)
IDENTIFICATION OF PRIMARY SITE BY GENETIC PROFILING
(MICROARRAYS) FROM ALL PUBLISHED CUP SERIES
Years of Publications
: 2005- 2007
No of Samples
Biological Assignment of
Primaries (Accuracy)
: > 500 (cDNA)
Primary Sites Identified
:
Breast
Pancreas
Bowel
Lung
Genital system
15 %
12.5 %
12 %
11.5 %
9%
Liver/bile duct
Kidney / adrenals
Bladder / ureter
Stomach
Other
8%
6%
5%
3%
18 %
: 50 – 87 %
WHAT IS THE OPTIMAL
THERAPEUTIC APPROACH OF
CANCER OF UNKNOWN PRIMARY ?
Overall comparative results of chemotherapy in
CUP patients. A review of all phase II non –
randomized studies
Platinum / taxane –
based combinations
5-FU / Anthracycline
combinations
Platinum based
combinations
No articles
12
28
Years
1964 - 1993
1983 - 2009
No patients
738
1238
1317
Response Rate %
(mean )
16.8
33.5
39.5
Mean Survival
(months)
6.7
8.4
11.4
18
1997 - 2010
DO WE HAVE EFFECTIVE DRUGS
FOR CANCER OF UNKNOWN
PRIMARY
OR
WE JUST HAVE RESPONSIVE
SUBSETS OF PATIENTS ?
WHAT IS CANCER OF UNKNOWN PRIMARY ?
Lung-hidden CUP
Kidney-hidden CUP
Pancreas-hidden CUP
Gastric-hidden CUP
Liver-hidden CUP
Colon-hidden CUP
Prostate-hidden CUP
Breast-hidden CUP
FAVOURABLE
OR
GOOD PROGNOSIS SUBSETS
CUP
UNFAVOURABLE
OR
POOR PROGNOSIS SUBSETS
THE
FAVOURABLE SUBSETS
OR
GOOD PROGNOSIS SUBSETS
Favourable
Subsets
Pavlidis N & Pentheroudakis G.
The Lancet 379 : 1428-35, 2012
1. Poorly differentiated carcinoma with midline distribution
(extragonadal germ cell syndrome).
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).
7. Adenocarcinoma with a colon-profile (CK 20+, CK 7-, CDX 2+)
8. Isolated inguinal adenopathy (squamous carcinoma).
9. Patients with a single, small, potentially resectable tumor.
CHARACTERISTICS OF PATIENTS WITH POORLY
DIFFERENTIATED CUP
GENDER / AGE
: Men / < 50 yrs
TUMOR INVOLVEMENT
: Mediastinum
Retroperitoneum
Lungs
Lymph nodes
TUMOR MARKERS
: Elevated serum levels of β-HGC or AFP
CLINICAL EVOLUTION
: Rapid tumor growth
RESPONSE TO Rx
: Favourable response to Cisplatin - based
chemotherapy. RR 50% (CRs: 15-25%)
SURVIVAL
: Median : 13 months
15% long – term survivors
Cancer Treatment Reviews ,
37 (2) 120-6, 2011
Cancer of Unknown Primary Patients with Midline Nodal Distribution:
midway between poor and favourable prognosis ?
Pentheroudakis G, Stoyianni A, Pavlidis N.
Literature Review = N 714 pts,
ORR : 35 – 65 % ,
Survival (median) : 12 mos
N
: 64 patients
ORR (to platinum )
: 48% (CRs : 11%)
Survival
: 12 mos
2-yr Survival
: 18%
PERITONEAL CARCINOMATOSIS IN
FEMALES
T H E NAT U RAL HIS T O RY
Incidence
10 % of invasive serous ovarian Ca, 10% of CUP
patients
Mean Age ( yrs )
60 ( 25 – 80 )
Clinical Picture
Abdominal distension, pelvic masses, ascites
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
OF PERITONEAL CAVILY
( 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 %
Crit Rev Oncol Hematol 75: 27-42, 2010
Serous Papillary Peritoneal Carcinoma:
Unknown primary tumour, ovarian cancer
counterpart or a distinct entity? A systematic review
G. Pentheroudakis, N. Pavlidis
Years
:
No Pts :
1980 – 2008 (25 studies)
SPPCs 579
SOCs 1408
ORR
OS (median)
SPPCs
SOCs
71%
70%
24,4 mos
29 mos
SPPC = Serous Papillary Peritoneal Carcinoma
SOC = Serous Ovarian Carcinoma
ISOLATED AXILLARY NODAL METASTASES
FROM AN OCCULT PRIMARY BREAST
CANCER
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/%,
Nodal status
: N1 : 48%
Simultaneous distant mets : 2%
HER2 31%
> N1 : 52%
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 RECOMMENDATIONS
AXILLARY LYMPH NODE
Surgical
Compatible with
Breast Cancer
Mammogram
U/S
MRI
+ve for Breast Cancer
Standard treatment
Type III level of evidence
Biopsy
Other Neoplasm
-ve for Breast Cancer
Complete Axillary Dissection
± BC Surgery + Radiotherapy
Chemotherapy or hormonotherapy
depending on age and menopausal status
SQUAMOUS CELL CANCER INVOLVING
CERVICAL LYMPH NODES
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).
Survival :
•
5-year survival 35–50%.
•
Documented long term disease – free survivors.
POORLY DIFFERENTIATED
NEUROENDOCRINE CARCINOMAS
Treatment:
Platinum – based or
paclitaxel / carboplatin – based
chemotherapy
Response :
50 – 70% ( CR : 25% )
Survival:
Median : 14.5 months
3-yr
: 24%
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)
Ioannina University Hospital Experience
N
: 15
PS 0-1 : 73 %
Metastases
Liver only : 47 %
Histology
Poorly – differentiated : 71.5 %
Well – differentiated : 28.5 %
Octreoscan
Positive : 40 % Negative : 60 %
Treatment 1st line
Platinum - based
Somatostatin analogs
Other
67 %
20 %
13 %
Survival
Median
1-year
Poorly – differ.
Well - differ.
18 months
54.5 %
15 months
24 months
OTHER 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 SUBSETS
OR
POOR PROGNOSIS SUBSETS
Pavlidis N & Pentheroudakis G.
The Lancet 379 : 1428-35, 2012
UNFAVOURABLE SUBSETS
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
Greco F, Pavlidis N. Semin Oncol, 2009
THE SUBSET OF
ADENOCARCINOMA
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
CUP PATIENTS WITH LIVER METASTASES
No of trials
No of patients
Response rate
Median survival
:
:
:
:
5 (1991, 1998, 2002, 2005, 2008)
711
< 20%
5.5 months
Bull Cancer 1991, J Clin Oncol 1998, Clin Radiol 2002,
Gastroent Clin Biol 2005, Cancer Treat Rev 2008
DO WE HAVE ANY EDIVENCE THAT
TARGETED TREATMENT IS DRASTIC
IN CUP PATIENTS ?
J Clin Oncol 2007 May 1;25(13):1747-52
No Patients :
47 (previously treated or poor-prognosis)
Treatment :
Bevacizumab 10 mg/kg q 2wks
Erlotinib
150 mg p.o. daily
Results :
10% PR
61% SD
Survival : Median 7.4 mos
1-year 33%
Oncologist 2009, 14(12): 1189-97
No Patients :
60
Regimen :
Carboplatin / paclitaxel / Bevacizumab / Erlotinib
As first-line and maintenance (Bev/Erlot)
Treatment :
49 pts completed 4 cycles
44 pts continued maintenance bevacizumab/erlotinib
Results :
53% major responses
41% stable disease
PFS - median : 8 mos
1-year : 38%
Survival – median: 12.6 mos
2-year : 27%
DOES THE IDENTIFICATION OF
PRIMARY SITE BY MOLECULAR
PROFILING IMPROVE PATIENTS’
OUTCOME ?
?
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, MD1,2; Mark S. Rubin, MD1,3; David R. Spigel, MD1,2; Samuel
Raby1; Thabiso Chirwa1; Raven Quinn, MS1; Catherine A. Schnabel, Ph.D.4; Mark
G. Erlander, Ph.D.4; John D. Hainsworth, MD1,2
1Sarah
Cannon Research Institute (SCRI), Nashville, TN ; 2Tennessee Oncology, PLLC,
Nashville, TN; 3Florida Cancer Specialists/SCRI, Ft Myers, FL; 4bioTheranostics, Inc., San Diego,
CA
Patient Flow Diagram
Patients enrolled
N = 289
Successful assay
N = 252
Insufficient tissue for assay
N = 37
Off study
Candidate for treatment
N = 223
Not a treatment candidate
N = 29
Off study
Received empiric CUP therapy
N =29
Received site-specific therapy directed by assay
results
N = 194
Received site-specific therapy for more
responsive tumor types
N = 115
PRESENTED BY: F. Anthony Greco, MD
Received site-specific therapy for
less responsive tumor types
N = 79
SITE SPECIFIC TREATMENTS
Predicted Tissue of Origin
Treatment
Breast
Taxane/bevacizumab
Colorectal
FOLFOX (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
PRESENTED BY: F. Anthony Greco, MD
TISSUE OF ORIGIN PREDICTED BY MOLECULAR ASSAY (N = 252)
Others
Number of Patients (%)
52 (21%)
31 (12%)
28 (11%)
27 (11%)
12 (5%)
12 (5%)
11 (4%)
10 (4%)
9 (4%)
8 (3%)
6 (2%)
6 (2%)
5 (2%)
4 (2%)
4 (2%)
4 (2%)
18 (10%)
PRESENTED BY: F. Anthony Greco,
MD
Predicted Tissue of Origin
Biliary tract (gallbladder, bile ducts)
Urothelium
Colorectum
Non-Small-Cell lung
Pancreas
Breast
Ovary
Gastroesophageal
Kidney
Liver
Sarcoma
Cervix
Neuroendocrine
Prostate
Germ Cell
Skin-squamous
SURVIVAL IN 223 TREATED PTS AND IN SUBSETS
Patient Group
All treated
Assay - directed treatment
Empiric treatment
Number Median survival (mo.)
223
10.8
194
29
12.5, p=0.02
4.7
115
79
13.4, p=0.04
7.6
45
12
26
23
10
10
6.8
8.2
12.5
15.9
29.6
NYR (>24)
Tumor type*
Treatment responsive
Less treatment responsive
Individual tumor types
Biliary tract
Pancreas
Colorectal
NSCLC
Ovary
Breast
NYR = not yet reached; *Includes 194 patients who received assay-directed treatment
PRESENTED BY: F. Anthony Greco, MD
OVERALL SURVIVAL : Assay-directed treatment vs. empiric
treatment
Median Survival (mo)
12.5
4.7
Overall survival Probability
Assay-directed (N=194)
Empiric (N=29)
p = 0.02
Time (months)
Empiric Treatment
Assay-directed treatment
PRESENTED BY: F. Anthony Greco, MD
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 France
on molecular diagnosis of the
primary
STEPS IN DIAGNOSTIC AND THERAPEUTIC MANAGEMENT
DIAGNOSIS OF METASTATIC CARCINOMA (by histopathology)
SEARCH
FOR PRIMARY SITE
STEP I
Clinical, immunohistochemistry, imaging, endoscopy studies
STEP II
RULE-OUT POTENTIALLY TREATABLE OR CURABLE TUMORS
(Immunohistochemistry or other studies)
i.e. Breast
STEP III
Cancer, Germ-cell Tumors, Lymphomas
CHARACTERIZE THE SPECIFIC CLINICOPATHOLOGICAL ENTITY
TREAT 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]
89
THE IOANNINA CUP TEAM
Thank you