R2 김재민 / Prof. 정재헌 Journal conference 1

Recommended treatment for carcinoma of unknown primary site (CUP) :  empiric chemotherapy taxane/platinum or gemcitabine/platinum regimen  modest benefits are achieved  survival of this group : poor (median survival, 9 months) : accurate identification of the tissue of origin and subsequent site-specific therapy will result in improved treatment for patients with CUP INTRODUCTION INTRODUCTION 2

Molecular tumor profiling new diagnostic technique by detecting site-specific gene expression profiles → enables prediction of a tissue of tumor origin reverse transcriptase polymerase chain reaction (RT-PCR) gene microarray techniques tested in metastatic carcinomas of known primary → identify the tissue of origin in approximately 85% Retrospective studies : prediction of the tissue of origin - in most cases : most molecular predictions - consistent with clinical and pathologic features : in a small series of patients - primary site detected - correctly predicted in 75%. INTRODUCTION INTRODUCTION 3

No prospective evidence is yet available In this prospective trial molecular tumor profiling was performed on biopsy specimens(CUP) When a tissue of origin was predicted → standard site-specific therapy INTRODUCTION INTRODUCTION 4

Prospective, phase II trial in 14 sites in the Sarah Cannon Oncology Research Consortium Patients  Dx of CUP after standard evaluation  Histologies  ECOG performance status: 0~2  no previous systemic therapy  measurable or evaluable disease(RECIST)  Exclusion: specific treatable CUP syndrome extragonadal germ cell syndrome neuroendocrine carcinoma adenocarcinoma isolated to axillary lymph nodes (women) peritoneal carcinomatosis (women) squamous carcinoma limited to cervical, supraclavicular, or inguinal lymph nodes single resectable metastasis PATIENTS AND METHODS PATIENTS AND METHODS 5

92-gene assay (CancerTYPE ID; bioTheranostics, San Diego, CA) prediction of the origin → standard site-specific therapy for advanced cancer If the assay was completed but unable to predict a tissue of origin → patients received standard empiric chemotherapy for CUP. re-evaluated for response after completion of 2 cycles of therapy Study Plan Study Plan 6

7 CancerTYPE ID is a standardized, objective molecular test based on the differential expression of 92 genes, that classifies tumors by matching the gene expression pattern of a patient’s tumor tissue to a database of known tumor types and histolo gical subtypes. CancerTYPE ID’s database includes 2,206 tumors from multiple tumor banks, selected to provi de broader and deeper representation of the heterogeneity of tumors. The 92-gene assay doe s not overlap with IHC markers, providing complementary data to standard tumor diagnosis. CancerTYPE ID uses real-time reverse transcription polymerase chain reaction (RT-PCR). A very low copy number of RNA molecules can be detected, thus reducing the sample tissue required for testing. Testing is conducted and results are gene rated at bioTheranostics' CAP-accredited, CLIA-certified laboratory.

Study Plan Study Plan 8

successful prediction rate impact of the molecular assay prediction on the efficacy of therapy for patients with CUP - overall survival Statistical Consideration Statistical Consideration 9

RESULTS ~ %

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RESULTS 12 Prediction: 98% 55%

RESULTS 13 88% 87%

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~2008 for 928 pts 8.9

DISCUSSION DISCUSSION 21 subgroups with specific diagnoses - relatively small → not possible to make definitive conclusion randomized phase III trial - potential confounding factor cancer types that are not markedly impacted ovary, breast, NSCLC, bladder - empiric CUP Tx = site-spicific Tx would take years to complete

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CONCLUSIONS CONCLUSIONS Molecular tumor profiling predict a tissue of origin in most patients with CUP median survival 12.5months for assay directed site specific Tx - longer than previous results using empirical CUP regimens more responsive tumor type - longer survival should be a part of CUP standard evaluation contributes to the management of CUP patients 23