1. CUP is a clinico-pathological syndrome of many specific cancer
types and predictable responses to therapies once classified
Alwin Krämer
Clinical Cooperation Unit
Molecular Hematology/Oncology
German Cancer Research Center and
Dept. of Internal Medicine V, University of Heidelberg

2. Patients with Disseminated Adeno- or Undifferentiated CUP
Have Low Survival Rates
Minnie Pearl Cancer Research Network CUP Patients Treated in Phase II Studies
Survival
1.0
0.8
0.6
0.4
0.2 12 24 36 48 60 72 84 96
108
120
1 year survival: 38%
5 year survival: 10%
10 year survival: 8%
Median survival: 9.1 months
N = 396
Greco, F.A., Hainsworth, J.D.: Cancer of unknown primary site, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 9). Philadelphia, P.A., J.B. Lippincott, 2011, pp

3. Primary Sites Determined at Autopsy
884 Patients with Cancer of Unknown Primary
12 Studies,
0.8% Breast
1.2% Bladder/Ureter
10% Other
6% Stomach
27% Lung
7% Genital system
7% Bowel
8% Liver/Bile duct
8% Kidney/Adrenal
24% Pancreas
Pentheroudakis, Greco, Pavlidis, Eur J Cancer 2007

4. CUP Subsets – ESMO Classification
Patient with a carcinoma of unknown primary (CUP)
Favorable prognosis CUP subset
Poor prognosis CUP subset
Women with isolated axillary lymph node metastases from adenocarcinoma
Women with papillary serous carcinoma restricted to the peritoneum
Squamous cell carcinoma restricted to cervical / inguinal lymph nodes
Adenocarcinoma with lower gastrointestinal profile
Poorly differentiated CUP with midline distribution
Neuroendocrine CUP
Metastatic melanoma of unknown primary
Men with osteoblastic metastases and elevated serum prostate-specific antigen
CUP restricted to a single metastatic site
PS ≤ 1
Normal LDH
PS ≥ 2 and / or
Elevated LDH
Favorable prognosis: Median survival =
12 months
Poor prognosis: Median survival =
4 months
Consider 2-drug chemotherapy
Chemotherapy or best supportive care
Specific treatment
Fizazi et al., on behalf of the ESMO Guidelines Committee: Cancers of unknown primary site: ESMO
clinical guidelines for diagnosis, treatment and follow-up. Ann Oncol. 26: v133-v138, 2015

5. Overall Survival in Patients with CUP Syndrome
Median survival is ~8 to 12 months and depends on several prognostic factors1
Select patients with favourable subsets of CUP have a median overall survival time of 12 to 36 months1 4 8 12 16 20 24 28 32 36
Time since diagnosis (months)
The percentage of cancers diagnosed as CUP has decreased, however, this has not been matched with an improvement in median survival2
CUP: cancer of unknown primary. 1. NCCN Guidelines: Occult Primary (CUP). Version ; 2. Urban, D. et al. (2013) Br J Cancer 109:

6. CUP Subsets – ESMO Classification
Known primary
Favorable prognosis CUP subset
Median overall survival
Median overall survival
Women with isolated axillary lymph node
metastases from adenocarcinoma
Women with papillary serous carcinoma
restricted to the peritoneum
Adenocarcinoma with lower gastrointestinal
profile
Poorly differentiated CUP with midline
distribution
Neuroendocrine CUP
CUP restricted to a single metastatic site
Mean 5-year survival
rate 72%
Mean 5-year survival
rate 85%
36 months
38 months
20-24 months
24 months
12 months
15.5 months
16 months
33 months
Pavlidis and Pentheroudakis, Lancet 379: , 2012

7. Gene Expression Profiling to Predict the Tissue of Origin
and Direct Site-specific Therapy in CUP Patients
Hainsworth et al., J Clin Oncol 31: , 2013

8. Gene Expression Profiling to Predict the Tissue of Origin
and Direct Site-specific Therapy in CUP Patients
Overall Survival
Hainsworth et al., J Clin Oncol 31: , 2013

9. DNA Methylation Profiling in CUP
DNA methylation profiling to predict the
tissue of origin and direct site-specific therapy in CUP patients
n=31
n=61
Retrospective analysis
p=0.0051
Moran et al., Lancet Oncol 2016

10. Gene Expression Profiling in CUP
Molecular Characterization
Gene Expression Profiling Identifies Responsive Patients
Treated with Carboplatin, Paclitaxel and Everolimus
Response rate
Progression-free survival
Overall survival
Yoon et al., Ann Oncol 2016

11. Overall Survival and Progression-free Survival
Hayashi et al., J Clin Oncol 2019

12. Clonal Relationship Between Prior Cancer and Presumed CUP⅔
Consecutive CUP cases
8/2016 – 6/2018
n = 175
Antecedent malignancy
44 /175
25.1% ⅓
Bochtler et al., Int J Cancer 2019