cup: treatment by molecular profiling george ... · cup therapeutic approach •diagnostic approach...
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CUP
George Pentheroudakis
Professor of Oncology
Medical School, University of Ioannina
Greece
Characteristics
• Clinical absence of primary
• Especially aggressive
• Early dissemination
• Multiple metastases- unpredictable metastatic pattern
CUP Staging
CUP Therapeutic Approach
• Diagnostic approach for primary tumor
identification
• Rule out potentially treatable or curable tumors
• Identify favorable subsets – apply site specific treatment
• Unfavorable subsets- palliative empiric chemotherapy
Favorable subsets• Poorly differentiated carcinoma with midline nodal distribution
(extragonadal germ cell syndrome).
• Women with papillary adenocarcinoma of peritoneal cavity.
• Women with adenocarcinoma involving only axillary lymph nodes.
• Squamous cell carcinoma involving cervical lymph nodes.
• Poorly differentiated neuroendocrine carcinomas.
• Men with blastic bone metastases PSA+ (adenocarcinoma).
• Adenocarcinoma with a colon-profile (CK 20+, CK 7-, CDX 2+)
• Isolated inguinal adenopathy (squamous carcinoma).
Pavlidis N & Pentheroudakis G. The Lancet 379 : 1428-35, 2012
IS THIS REALLY
CUP?
Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet. 2012 Apr 14;379(9824):1428-35.
Unfavorable Subsets
• Adenocarcinoma metastatic to the liver or other organs
• Non-papillary malignant ascites (adenocarcinoma)
• Multiple cerebral metastases (adeno or squamous Ca)
• Multiple lung/pleural metastases (adenocarcinoma)
• Multiple metastatic bone disease (adenocarcinoma)
• Squamous – cell carcinoma of the abdominal cavity
Lazaridis G, Pentheroudakis G et al .Cancer Treat Rev.
2008 Dec;34(8):693-700
VISCERAL CUP
What do we mean by “MOLECULAR
PROFILING ASSAYS”?
1. FIND THE TISSUE OF ORIGIN
Molecular assays may identify a primary site of
origin but does primary-specific therapy improve
outcomes?
2. FIND THE MOLECULAR TARGET
Does the screening for, and targeting of molecular
aberrations improve outcomes?
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Premise of “tissue of origin” classifierexample of Cancer Genetics platform
CUP
“Similarity Scores” a
Colorectal 88.2
Pancreas 4.4
NSCLC 2.3
Breast 2.1
Gastric 1.2
Kidney 0.6
HCC 0.3
Ovarian 0.3
Soft Tissue Sarcoma 0.1
NHL 0.1
Thyroid 0.1
Prostate 0.1
Melanoma 0.1
Bladder 0.1
Testicular Germ Cell 0.0
Adapted from
Cancergenetics.com
RNA profile2,000 genes
Compare
with known
tissue
profiles
a Similarity Scores of all possible primaries add up to 100
Premise: Each tumor
type has a distinct
molecular profile
Platformmolecule
class# genes
# of claimed
distinguishable
cancer types
BioTheranostics mRNA 92 ~50
Cancer Genetics mRNA ~2,000 15
Veridex mRNA 10 6
Agendia mRNA 495 9
Rosetta microRNA 48 25
EPICUPDNA
methylation
485,577 CpG
sites a38
a Examined in development phase (Moran et al 2016)
Dolled-Filhart and Rimm 2012 Cancer Cytopatholology
Research attention has focused on large panels of markers to identify tissue of origin
TOO classifiers: 10-2,000 genes analyzed simultaneously
Sarah Cannon trial examined TOO classifier-directed therapy
(enrolled 2008-2011)
a Biotheranostics (92-gene microarray)b Total of 26 different tissues of origin were predicted
CUP Treatment-naïve289 enrolled
TOO testing a
CRC FOLFOX(IRI) + bev
Ovary Carbo/Taxol + bev
Pancreas Gem + erlotinib
Prostate Androgen ablation
Others b Standard 1st-line Rx guidelines
TOO classifier-directed therapyNon-randomized
Hainsworth et al. JCO 2012
194 Received classifier-directed Rx (67% 194/289])
252 Successful assay (87% [252/289])
Varadhachary et al., Clin Cancer Res 2011
Hainsworth et al., J Clin Oncol 2013
Site-specific therapy for CUPs confers improved survival: Prospective studies
RCT to address whether TOO classifier-directed therapy can improve outcomes
French trial (GEFCAPI04)
Status: Enrolled ~200 pts (as of 04/2017)Estimated date to report primary outcome: 2018-2019
CUP (N = 223)
• Treatment-naïve
• Not limited to certain TOO profiles Gemcitabine
+ cisplatin
TOO testinga
with result unmasked
a Biotheranostics CancerTYPE ID. c Classifier-directed therapy is not publicly available
Data accessed from clinicaltrials.gov (NCT01540058) 4.11.2017
Classifier-directed therapy c
RPrimary
endpoint: PFS
TOO testinga
with result masked
Druggable targets in CUP tumors
➢ Foundation One
• Mutation analysis of 236 genes and rearrangements in 19 genes (NGS)
• N = 200 CUP tumors
➢ Caris Life Sciences
• Mutation analysis of 47 genes (eg, NGS); IHC 23 markers; FISH/CISH of 7
genes
• N = 1,806 CUP tumors
• But for many genes, a small subset of tumors was analyzed
Ross et al. JAMA Oncology 2015
Gatalica et al Oncotarget 2014
NSG = next generation sequencing
IHC = immunohistochemistry
FISH/CISH = fluorescence in situ hybridization
CUP aberrationsConway, Br J Cancer, 2019 Jan;120(2):141-153.
Challenges of tumor-agnostic approach (SHIVA): First randomized trial comparing molecularly targeted vs other
in tumor-agnostic setting
Solid tumor(N = 741
screened)
Investigator choice d
Molecular profiling a
a Targeted NGS, IHC, copy number alterationb Most exclusions due to incomplete molecular profile (n ~240), no targetable alteration (n ~200), other (n~100).
Included only patients with molecular alteration in one of 3 pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK)c One of 10 regimens: erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus,
abiraterone, letrozole, tamoxifen.d Almost all received cytotoxic therapies (monotherapy, n=70; combination, n=19; none, n=3)
Molecularly targeted agent c
Primary endpoint
PFS
R
Targetable alteration identified
and randomized (n=195) b
Open
label
Le Tourneau et al Lancet Oncology 2015
SHIVA: Failed to meet primary endpoint of PFS
Potential reasons cited by investigators:
• Treatment based on single (vs multiple) molecular alteration
• Mostly monotherapy• Limited choice of
targeted agents a
a For example, dual MTORC inhibitor may be better than everolimus
to target PI3K/AKT/mTOR pathway
NOTE: only 2 patients in control arm received molecularly targeted agent
HR 0.88 (p =.41)
Molecular targeted
therapy
MD choice
RR = 4.1% experimental vs 3.4% control
*Tissue sample suitable for initial diagnosis of CUP at study site, confirmation of CUP diagnosis and generation of Foundation One comprehensive genomic profile at central
laboratory‡Sample suitable for analysis of circulating tumour DNA using FoundationACT assay
CUPISCO Trial
Inclusion criteria
• Histologically confirmed
CUP (non-specific subset)
• No prior lines of therapy
• ECOG PS 0–1
• ≥1 measurable lesion
N=790
Induction
Carboplatin + paclitaxel or
cisplatin + gemcitabine
(3 cycles)
Non-responders
PD or intolerable
toxicity
n=318 (40%)
Responders
CR, PR or SD
n=472 (60%)
Investigator choice
(following Molecular
Tumour Board advice)
n=354
Alectinib (ALK or RET rearrangements)
Erlotinib + bevacizumab (EGFR Mut+)
Trastuzumab + pertuzumab + continued
induction chemo (ERBB2)
Vismodegib (PTCH1, SUFU or SMO)
Vemurafenib + cobimetinib (BRAF MutV600)
Ipatasertib (AKT1 or PI3K)
Olaparib (BRCA1, BRCA2 or HRD)
Atezolizumab (TMB high or MSI-high)
Atezolizumab + continued induction
chemo (patients with no other option)
R
3:1
n=118
Investigator choice
(following Molecular
Tumour Board advice)Assigned as per randomised arm
Carboplatin + paclitaxel or
cisplatin + gemcitabine (3 cycles)Screening
Genomic profiling
Tissue* and blood‡
plus select biomarkers
(e.g. PD-L1)
Primary endpoint: pooled PFS from 9
molecularly guided regimens vs chemo in
responders to induction chemo [PFS1]
Secondary endpoint: OS
Category 1
Category 2
Mutational burden in CUP
• Evaluation of MSI and TMB in 5991 CUP tumours.
• High TMB varied by histological subtype but
ranged:
• 6.1% in neuroendocrine CUP
• 21.6% in squamous CUP.
• 2.9% MSI-H
• Chalmers et al, Genome Med. 2017; 9(1): 1–14.
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• 389 patients with CUP: tumour mutation burden (TMB), PDL1 status, MSI.
• 28% of samples had one or more factors that may indicate a response to immunotherapy.
• High PDL-1 expression was found in TIL (63%) and cancer cells (21%) with co-expression in 16% of cases
• Xiu et al, Ann Oncol. 2017; 28 (suppl_5): v22–v42.10.1093.
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Immune response in CUP
miRNA CUP SIGNATURE• N=150 CUP
• Compare the expression of a library of 900
microRNAs between:
- CUPs biologically classified
- Metastases from equivalent known primary
tumours (KPM)
• IS THERE A miRNA CUP SIGNATURE?
Pentheroudakis et al, Clin Exp
Metastasis 2013;30(4):431-9 24
Suggested use of Molecular AssaysClin Cancer Res 2013;19:4027-4033
CUP AlgorithmClinical Presentation
Initial Clinical/Diagnostic Evaluation and Biopsy
Standard Pathology, Immunohistochemistry Stains
Anatomical Primary Site Not Identified Anatomical Primary Site Identified
Favorable Subset CUP Site Specific Therapy
Specific Treatment for Subset
Tissue of Origin Molecular Profiler on Selected Tumors
Single Tissue of Origin Diagnosed Single Tissue of Origin Not Diagnosed
Clinical Trial or
Site Specific Therapy
Clinical Trial or Pick the Target NGS assay or
Empiric Therapy
Poor Risk
THANK YOU
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