Using Advanced Molecular Profiling to Identify the Origin of and Tailor Treatment for an Intracranial Mass of Unknown Primary

10530 Background: Tumor profiling is an emergent technique to determine tissue of origin in CUP patients. However, the value of these predictions in improving treatment efficacy is unknown. In this prospective trial, we used tumor profiling results to direct site-specific therapy for CUP pts. Methods: A 92-gene RT-PCR assay (CancerTYPE ID; bioTheranostics, Inc.) was performed on tumor biopsies from previously untreated CUP pts who consented. When a tissue of origin was predicted, pts who were treatment candidates were assigned standard site-specific first-line therapy. Results: Between 10/08 and 12/11, 289 pts were enrolled, 252 had successful assays performed, and 247 (98%) had a tissue of origin predicted. 224 pts were eligible for treatment; 197 pts received assay-directed treatment. 120 of 224 treated pts (54%) had assay diagnoses of tumor types known to derive substantial benefit from standard site-specific treatment (bladder 27, colorectal 26, NSCLC 24, breast 10, ovary 10, kidney 9, prostate 4, germ cell 4, others 6 (3 sites), while 104 pts (46%) had assay diagnoses of relatively resistant tumors (biliary tract 45, pancreas 12, gastroesophageal 10, liver 7, sarcoma 5, cervix 5, others 20 (8 sites). Median OS for all treated pts was 10.8 months (mos); OS for 197 pts with assay-directed treatment was 12.2 mos (versus 6.0 mos for 27 pts receiving empiric therapy). Median OS was better in the 120 pts with assay diagnoses of more responsive tumor types (12.8 vs 7.4 mos; p = .027). Median OS (mos) in specific subgroups: pancreas 9, kidney 12, colon 12, NSCLC 16, ovary 30. Conclusions: This is the first prospective trial in which molecular profiling has directed site-specific therapy in CUP pts. Assay-directed therapy in 197 pts produced a median OS (12.2 mos) that compares favorably with previous empiric CUP therapy. CUP pts predicted to have more responsive tumor types had longer survival compared to less responsive types, suggesting accurate identification by the assay. These results strengthen the rationale for molecular profiling in CUP management.

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New Strategies for Carcinoma of Unknown Primary: The Role of Tissue-of-Origin Molecular Profiling

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-12-3030 ◽

2013 ◽

Vol 19 (15) ◽

pp. 4027-4033 ◽

Cited By ~ 26

Author(s):

Gauri Varadhachary

Keyword(s):

Molecular Profiling ◽

Unknown Primary ◽

Carcinoma Of Unknown Primary ◽

Tissue Of Origin ◽

New Strategies

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Unknown primary cancer (UPC): Accuracy of tissue of origin prediction by molecular profiling

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.11070 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 11070-11070

Author(s):

F. A. Greco ◽

D. R. Spigel ◽

D. A. Yardley ◽

M. Erlander ◽

X. Ma ◽

...

Keyword(s):

Molecular Profiling ◽

Primary Site ◽

Unknown Primary ◽

Rt Pcr ◽

Pcr Assay ◽

Arch Pathol ◽

Pcr Diagnosis ◽

Formalin Fixed Paraffin ◽

Diagnostic Biopsy ◽

Formalin Fixed Paraffin Embedded

11070 Background: Molecular profiling may be useful to identify the primary site and direct therapy for patients (pts) with UPC. Since most UPC pts never have a primary site identified, the accuracy of molecular profiling diagnoses are difficult to verify. We identified a group of UPC pts who had a primary site subsequently identified during their clinical course, and performed a 92-gene real time polymerase chain reaction (RT-PCR) assay (Arch Pathol Lab Med 130:465, 2006) on tissue from the initial diagnostic biopsy. We then compared the RT-PCR diagnosis with the subsequent clinical diagnosis. Methods: 38 of 501 UPC pts (7%) seen between 2000 and 2008 had their primary tumor subsequently identified during life. 24 of the 38 pts had tissue biopsies (excluding FNA cytology) and are the subject of this study. The RT-PCR assay was performed on unstained slides from the formalin-fixed, paraffin-embedded (FFPE) initial diagnostic biopsy, and the assay predictions were compared to the actual primary sites (found later). No clinical or pathologic data (other than sex, biopsy site, and 1 H&E stained slide) were used in the prediction of the primary site. Results: 16 of 24 assays were successful (8 had no tumor or RNA in the material). 11 of 16 predictions of the site of origin (68%) were correct, corresponding to the actual primary sites found 3–58 months (median 8.5 months) after the initial diagnosis of UPC. Primary sites correctly identified included breast 2, ovary/peritoneal 4, NSCLC 1, colorectal 2, gastric 1, melanoma 1. 3 predictions were inaccurate (colorectal, testicular, sarcoma) in patients with gastroesophageal, pancreas and NSCLC, respectively. 2 assays were unclassifiable. Conclusions: RT-PCR performed on FFPE initial diagnostic tissue was accurate in predicting the primary site of origin in 11 of 16 pts with UPC who eventually had their primary site identified clinically. These data provide a direct validation of the reliability of this RT-PCR assay in predicting the primary site in pts with UPC. When used in concert with clinical features and IHC stains, molecular profiling may provide the basis for more successful site-directed therapy for many of these pts. Prospective studies of RT-PCR in UPC are ongoing. [Table: see text]

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Molecular Profiling in Unknown Primary Cancer: Accuracy of Tissue of Origin Prediction

The Oncologist ◽

10.1634/theoncologist.2009-0328 ◽

2010 ◽

Vol 15 (5) ◽

pp. 500-506 ◽

Cited By ~ 74

Author(s):

F. Anthony Greco ◽

David R. Spigel ◽

Denise A. Yardley ◽

Mark G. Erlander ◽

Xiao‐Jun Ma ◽

...

Keyword(s):

Molecular Profiling ◽

Unknown Primary ◽

Primary Cancer ◽

Tissue Of Origin

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Treatment of carcinoma of unknown primary site (CUP) directed by molecular profiling diagnosis: A prospective, phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.10540 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 10540-10540 ◽

Cited By ~ 6

Author(s):

J. D. Hainsworth ◽

D. R. Spigel ◽

M. S. Rubin ◽

R. V. Boccia ◽

E. P. Fox ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Molecular Profiling ◽

Primary Site ◽

Unknown Primary ◽

Unknown Primary Site ◽

Carcinoma Of Unknown Primary ◽

Prospective Phase

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Observational study of real world clinical performance of microrna molecular profiling for cancer of unknown primary (CUP).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22173 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22173-e22173 ◽

Cited By ~ 2

Author(s):

Mats Olot Sanden ◽

Robert Wassman ◽

Karin Ashkenazi ◽

Hila Benjamin ◽

Yael Spector ◽

...

Keyword(s):

Real World ◽

Clinical Setting ◽

Test Performance ◽

Clinical Performance ◽

Molecular Profiling ◽

Upper Body ◽

Unknown Primary ◽

Tumor Type ◽

The Real ◽

Tumor Types

e22173 Background: Molecular profiling of CUP may effectively identify the underlying tumor type and potentially influence treatment decisions and outcomes. A microRNA (miR) array has been shown in concordance studies at leading academic centers to perform well in correctly identifying the tumor of origin in CUP. This series of consecutive referrals tested in a CLIA-laboratory extends these findings to the real world clinical setting. Methods: MicroRNA was isolated from 258 consecutive specimens referred to Rosetta Genomics, analyzed on a 64 miR-based array, and interpreted for any of 42 specific tumor types as previously described. The laboratory medical director routinely collected follow-up information on correlation of test prediction with other clinical information, pathology findings, supplemental IHC, treatment response, and clinical course as well as physician perception of relevance and utility of test result. This information was scored categorically into 3 classes of concordance depending on agreement with clinical and/or pathological data. The composite data was de-identified and analyzed for assessment of overall test performance in this real world clinical setting. Results: Of 258 specimens submitted 90% were paraffin embedded tissue (FFPE). Sufficient tumor material was received in 217 (85%) cases, of which 192 (88%) were successfully processed and reported with a mean TAT of 7 days. The most common result was colorectal (12%), followed by breast (10.4%), upper body squamous cell (7.3%), ovarian (6.8%), and biliary tract/pancreatic (6.8%); and the remaining 109 cases (57%) represented 30 additional tumor types. Overall the concordance with the clinical and/or pathological best final diagnosis was 86%, and when the reporting algorithm yielded a single diagnosis (51% of cases) the concordance was 89%. Clinical utility as measured by consideration of a shift in therapy or significantly increased decisional certainty for therapy was observed in approximately 70% of the cases. Conclusions: MicroRNA analysis in CUP cases performs comparably in the real world setting to that previously reported in academic studies and adds information of value to the management of patients.

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