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