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CANCER OF UNKNOWN PRIMARY SITE

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Title: CANCER OF UNKNOWN PRIMARY SITE


1
CANCER OF UNKNOWN PRIMARY SITE
NICHOLAS PAVLIDIS, MD, PhD, FRCP (Edin)
  • PROFESSOR OF MEDICAL ONCOLOGY
  • MEDICAL SCHOOL, UNIVERSITY OF IOANNINA
  • GREECE

Barcelona , June 2012
2
CANCER OF UNKNOWN PRIMARY ( CUP )
  • 1) DEFINITION
  • EPIDEMIOLOGY
  • BIOLOGY
  • 4) PATHOLOGY
  • 5) NATURAL HISTORY
  • 6) DIAGNOSTIC APPROACH
  • 7) TREATMENT

3
IS THERE A DEFINITION FOR CANCER OF UNKNOWN
PRIMARY ORIGIN ?
4
THE DEFINITION
In 1970s
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.
5
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).

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11
WHAT IS THE INCIDENCE OF CANCER OF UNKNOWN
PRIMARY SITE ?
12
EPIDEMIOLOGY OF CANCER OF UNKNOWN
PRIMARY
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 -
13
THE BIOLOGY OF CANCER OF UNKNOWN PRIMARY
14
Hypothesis A
  • CUP does not undergo type 1 progression
    (from a premalignant lesion to malignant)
  • b u t
  • 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
15
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 t o
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
16
TRANSLATIONAL RESEARCH ON CUP BIOLOGY
  • Chromosomal Instability
  • Oncogenes Oncoproteins
  • Tumour and Metastasis Suppressor Genes
  • Angiogenesis
  • Metalloproteinases
  • Hypoxia
  • Epithelial Mesenchymal Transition and Stemness
  • Signaling Pathways

17
TRANSLATIONAL RESEARCH IN CUP
Gene/ Molecule F i n d i n g s 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
18
Matrix Metalloproteinase
MMP-2 4 - None
MMP -9 36 - None
TIMP-1 44 - Adverse prognostic factor
Hypoxia
GLUT-1
HIF 1a
COX-2
Adverse prognostic factor in squamous
cervical CUP
25
-
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
19
Signaling Pathways
cMET 42 30 ? cMET favourable prognosis ? pMAPK adverse prognosis ? Notch-3 adverse prognosis
pMARK 54 - ? cMET favourable prognosis ? pMAPK adverse prognosis ? Notch-3 adverse prognosis
Notch 1-3 2-73 - ? cMET favourable prognosis ? pMAPK adverse prognosis ? Notch-3 adverse prognosis
Jagged 1 22 - ? cMET favourable prognosis ? pMAPK adverse prognosis ? Notch-3 adverse prognosis
PTEN 50 - ? p21 favourable prognosis ? pAKT or pRPS6 adverse prognosis pMAPK pAKT adverse prognosis
pAKT 73 - ? p21 favourable prognosis ? pAKT or pRPS6 adverse prognosis pMAPK pAKT adverse prognosis
pRPS6 60 - ? p21 favourable prognosis ? pAKT or pRPS6 adverse prognosis pMAPK pAKT adverse prognosis
p21 61 - ? p21 favourable prognosis ? pAKT or pRPS6 adverse prognosis pMAPK pAKT adverse prognosis
Cyclin D1 44 - ? p21 favourable prognosis ? pAKT or pRPS6 adverse prognosis pMAPK pAKT adverse prognosis
20
THE NATURAL HISTORY OF CANCER OF UNKNOWN
PRIMARY SITE
21
FUNDAMENTAL CHARACTERISTICS
  • Early dissemination
  • Clinical absence of primary at presentation
  • Aggressiveness
  • Unpredictable metastatic pattern

22
UNPREDICTABLE METASTATIC PATTERN
  • Refers to the differences in the incidence
    of metastatic sites at diagnosis between
    known and unknown primary carcinomas
  • E x a m p l e
  • Pancreatic cancer presenting as CUP has
    4-fold higher incidence to affect bones,
    and 30 incidence to appear with lung metastases.

23
Cancer of Unknown Primary Site
One or more Diseases ?
24
HISTOLOGICAL CLASSIFICATION
I N C I D E N C E
H I S T O L O G Y
A d e n o c a r c i n o m a Well to
moderately differentiated Poorly or
undifferentiated
 
50
35
S q u a m o u s c e l l c a r c i n o m a
 
10
U n d i f f e r e n t i a t e d ne o p l a s
m s Not specified carcinoma
Neuroendocrine tumors Lymphomas Germ
cell tumors Melanomas Sarcomas
Embryonal malignancies
5
 
25
CLINICOPATHOLOGICAL ENTITIES OF CUP
O R G A N
H 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
26
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 )
Lungs Pulmonary metastases Pleural effusion AdenoCa various diff AdenoCa M or P diff
W well, M moderately, P poorly, U
undifferentiated
27
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 U neoplasm with melanoma features.
W well, M moderately, P poorly, U
undifferentiated
28
WHAT IS THE OPTIMAL INVESTIGATIONAL
DIAGNOSTIC APPROACH FOR THE IDENTIFICATION OF
THE PRIMARY TUMOR ?
29
HOW DO WE SEARCH FOR THE PRIMARY ?
By HISTOPATHOLOGY
By IMAGING
By ENDOSCOPY
Immunohisto-chemistry
ENT panendoscopy
Conventional Radiology
PET- scans
Advanced Molecular Technology
Bronchoscopy
Mammography
Colonoscopy
Ultrasonography
Proctoscopy
CT- scans MRIs
Colposcopy
30
By HISTOPATHOLOGY
31
STEPS OF IMMUNOHISTOCHEMICAL DIAGNOSTIC
APPROACH FOR CUP
STEP 1 (Detects broad type of cancer)
  • Carcinoma AE 1/3 pancytokeratin
  • Lymphoma Common leucocyte antigen (CLA)
  • Melanoma S100, HMB45
  • Sarcoma S100, Vimentin

32
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

33
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

34
CYTOKERATINS (CKS)
  • Monoclonal antibodies against cytokeratin
    polypeptides CK7 and CK20

35
CK7 CK20
CK7 CK20
CK7 CK20 -
CK7 - CK20
CK7 - CK20 -
Urothelial tumors Ovarian mucinous
adenocarcinoma Pancreatic adenocarcinoma Cholangi
ocarcinoma
Lung adenocarcinoma Breast carcinoma Thyroid
carcinoma Endometrial carcinoma Cervical
carcinoma Salivary gland carcinoma Cholangiocarc
inoma Pancreatic carcinoma
Colorectal Carcinoma Merkel cell carcinoma
Hepatocellular carcinoma Renal cell
carcinoma Prostate carcinoma Squamous cell
small cell lung carcinoma Head neck carcinoma
36
MOLECULAR ANALYSIS Microarray Platforms
gt 80 90 accuracy
37
Gene expression profiling
A s s a y s
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
38
Accuracy of microRNA-based classification of
metastases of unknown primary.
Nicholas Pavlidis, George E. Pentheroudakis,
et al ASCO, May 2012
  • A b s t r a c t
  • 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.

39
By IMAGING
40
IMAGING STUDIES IN CUP
  • Imaging Study
  • Diagnostic Value
  • Chest X-ray
  • Barium studies
  • CT-scans
  • Mammography
  • MRI (breast)
  • FDG-PET SCAN
  • Prerequisite test
  • Useless
  • 40 accuracy / Guidance to biopsy
  • Low sensitivity
  • 60 accuracy
  • 43 accuracy / more sensitive for occult HN and
    Lung Ca

41
By ENDOSCOPY
42
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

43
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 in men with bone metastatic
    adenocarcinoma
  • ?-HCG AFP in men with an
    undifferentiated tumor
  • AFP 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.

44
HOW OFTEN CAN THE PRIMARY TUMOR BE
INDENTIFIED ?
45
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
46
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47
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)
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
48
IDENTIFICATION OF PRIMARY SITE BY GENETIC
PROFILING (MICROARRAYS) FROM ALL PUBLISHED
CUP SERIES
  • Years of Publications 2005- 2007

No of Samples gt 500 (cDNA)
Biological Assignment of
Primaries
(Accuracy) 50 87
Primary Sites Identified
Breast 15 Pancreas 12.5 Bowel 12
Lung 11.5 Genital system 9
Liver/bile duct 8 Kidney / adrenals 6
Bladder / ureter 5 Stomach
3 Other 18
49
WHAT IS THE OPTIMAL THERAPEUTIC APPROACH OF
CANCER OF UNKNOWN PRIMARY ?
50
Overall comparative results of chemotherapy
in CUP patients. A review of all phase II
non randomized 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
51
DO WE HAVE EFFECTIVE DRUGS FOR CANCER OF
UNKNOWN PRIMARY OR WE JUST HAVE RESPONSIVE
SUBSETS OF PATIENTS ?
52
2003
39 1990 2005,
DIAGNOSTIC AND THERAPEUTIC MANAGEMENT OF
CANCER OF AN UNKNOWN PRIMARY N. Pavlidis, E.
Briasoulis, J. Hainsworth, E.A. Greco
53
WHAT IS CANCER OF UNKNOWN PRIMARY ?
Lung-hidden CUP
Pancreas-hidden CUP
Kidney-hidden CUP
Gastric-hidden CUP
Liver-hidden CUP
Colon-hidden CUP
Breast-hidden CUP
Prostate-hidden CUP
54
FAVOURABLE OR
GOOD PROGNOSIS SUBSETS
CUP
UNFAVOURABLE OR POOR PROGNOSIS
SUBSETS
55
THE FAVOURABLE SUBSETS OR
GOOD PROGNOSIS
SUBSETS
56
1.  Poorly differentiated carcinoma with
midline distribution (extragonadal germ
cell syndrome).
Pavlidis N Pentheroudakis G. The
Lancet 379 1428-35, 2012
F 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).
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.
57
CHARACTERISTICS OF PATIENTS WITH POORLY
DIFFERENTIATED CUP
GENDER / AGE Men / lt 50 yrs
TUMOR INVOLVEMENT Mediastinum Retroperitoneum Lungs Lymph nodes
TUMOR MARKERS Elevated serum levels of ß-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
58
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
N 64 patients ORR (to
platinum ) 48 (CRs 11) Survival
12 mos 2-yr Survival 18
59
PERITONEAL CARCINOMATOSIS IN FEMALES
T H E N A T U R A L H I S T O R Y
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.
60
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
61
Serous Papillary Peritoneal
Carcinoma Unknown primary tumour,
ovarian cancer counterpart or a distinct
entity? A systematic review
Crit Rev Oncol Hematol 75 27-42, 2010
G. Pentheroudakis, N. Pavlidis
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
62
ISOLATED AXILLARY NODAL METASTASES FROM AN
OCCULT PRIMARY BREAST CANCER
63
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
gt N1 52 Simultaneous distant mets 2
64
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

65
TREATMENT RECOMMENDATIONS
AXILLARY LYMPH NODE
S u r g i c a l B i o p s y
Compatible with Breast Cancer
Mammogram U/S MRI
Other Neoplasm
ve for Breast Cancer
-ve for Breast Cancer
Complete Axillary Dissection BC Surgery
Radiotherapy
Standard treatment
Chemotherapy or hormonotherapy depending on
age and menopausal status
Type III level of evidence
66
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 3550. Documented long term disease free survivors.
67
POORLY DIFFERENTIATED NEUROENDOCRINE
CARCINOMAS
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 )
S u r v i v a l Median 14.5 months 3-yr 24
68
  • 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)

69
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 67
Somatostatin analogs 20 Other
13
Survival Median 18 months 1-year 54.5
Poorly differ. 15 months Well -
differ. 24 months
70
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

71
THE UNFAVOURABLE SUBSETS OR
POOR PROGNOSIS
SUBSETS
72
Pavlidis N Pentheroudakis G. The
Lancet 379 1428-35, 2012
U 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

73
Greco F, Pavlidis N. Semin Oncol, 2009
74
THE SUBSET OF ADENOCARCINOMA METASTATIC TO
THE LIVER
75
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) (N365) (N88) (N118) (N49) (N711)
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
76
OVERALL RESULTS OF CHEMOTHERAPY IN CUP
PATIENTS WITH LIVER METASTASES
  • No of trials 5 (1991, 1998, 2002,
    2005, 2008)
  • No of patients 711
  • Response rate lt 20
  • Median survival 5.5 months

Bull Cancer 1991, J Clin Oncol 1998, Clin
Radiol 2002, Gastroent Clin Biol 2005, Cancer
Treat Rev 2008
77
DO WE HAVE ANY EDIVENCE THAT TARGETED
TREATMENT IS DRASTIC IN CUP PATIENTS ?
78
J Clin Oncol 2007 May 125(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

79
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

80
  • DOES THE IDENTIFICATION OF PRIMARY SITE BY
    MOLECULAR PROFILING IMPROVE PATIENTS OUTCOME
    ?

?
WHAT IS THE EVIDENCE TODAY ?
81
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

82
Patient Flow Diagram
Patients enrolled N 289
Insufficient tissue for assay N 37 Off
study
Successful assay N 252
Not a treatment candidate N 29 Off study
Candidate for treatment N 223
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
Received site-specific therapy for less
responsive tumor types N 79
83
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
84
Tissue of origin predicted by Molecular
Assay (N 252)
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)
85
Survival in 223 Treated Pts and in
Subsets
Patient Group Number Median survival (mo.)
All treated 223 10.8

Assay - directed treatment 194 12.5, p0.02
Empiric treatment 29 4.7

Tumor type Tumor type Tumor type
Treatment responsive 115 13.4, p0.04
Less treatment responsive 79 7.6

Individual tumor types Individual tumor types Individual tumor types
Biliary tract 45 6.8
Pancreas 12 8.2
Colorectal 26 12.5
NSCLC 23 15.9
Ovary 10 29.6
Breast 10 NYR (gt24)
NYR not yet reached Includes 194 patients who
received assay-directed treatment
86
Overall Survival Assay-directed treatment
vs. empiric treatment
Median Survival (mo) Assay-directed (N194)
12.5 Empiric (N29)
4.7 p 0.02
Overall survival Probability
Time (months) Empiric
Treatment Assay-directed
treatment
87
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
88
STEPS IN DIAGNOSTIC AND THERAPEUTIC
MANAGEMENT
DIAGNOSIS OF METASTATIC CARCINOMA (by
histopathology)
  SEARCH FOR PRIMARY SITE Clinical,
immunohistochemistry, imaging, endoscopy
studies
STEP I
RULE-OUT POTENTIALLY TREATABLE OR
CURABLE TUMORS (Immunohistochemistry or
other studies) i.e. Breast
Cancer, Germ-cell Tumors, Lymphomas
STEP II
STEP III
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
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THE IOANNINA CUP TEAM
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