Oncotarget

Research Papers:

Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas

Roman Groisberg, David S. Hong, Vijaykumar Holla, Filip Janku, Sarina Piha-Paul, Vinod Ravi, Robert Benjamin, Shreyas Kumar Patel, Neeta Somaiah, Anthony Conley, Siraj M. Ali, Alexa B. Schrock, Jeffrey S. Ross, Philip J. Stephens, Vincent A. Miller, Shiraj Sen, Cynthia Herzog, Funda Meric-Bernstam and Vivek Subbiah _

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Oncotarget. 2017; 8:39254-39267. https://doi.org/10.18632/oncotarget.16845

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Abstract

Roman Groisberg1,2, David S. Hong1, Vijaykumar Holla3, Filip Janku1, Sarina Piha-Paul1, Vinod Ravi4, Robert Benjamin4, Shreyas Kumar Patel4, Neeta Somaiah4, Anthony Conley4, Siraj M. Ali6, Alexa B. Schrock6, Jeffrey S. Ross6, Philip J. Stephens6, Vincent A. Miller6, Shiraj Sen1,2, Cynthia Herzog5, Funda Meric-Bernstam1 and Vivek Subbiah1

1Department of Investigational Cancer Therapeutics (A Phase I Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

2Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

3Khalifa Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

4Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

5Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

6Foundation Medicine Inc, Cambridge, Massachusetts 02139, USA

Correspondence to:

Vivek Subbiah, email: vsubbiah@mdanderson.org

Keywords: sarcoma, targeted therapy, phase I trials

Received: January 29, 2017    Accepted: March 08, 2017    Published: April 05, 2017

ABSTRACT

Background: There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors. Complicating this is the extreme diversity, heterogeneity, and rarity of these neoplasms. Few therapeutic options exist for relapsed and refractory sarcomas. In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy. However, a systematic analysis of actionable mutations has yet to be completed. We analyzed genomic profiling results in patients referred to MD Anderson Cancer Center with advanced sarcomas to elucidate the frequency of potentially actionable genomic alterations in this population.

Methods: We reviewed charts of patients with advanced sarcoma who were referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling (CGP) of 236 or 315 cancer genes in at least 50ng of DNA. Actionable alterations were defined as those identifying anti-cancer drugs on the market, in registered clinical trials, or in the Drug-Gene Interaction Database.

Results: Among the 102 patients analyzed median age was 45.5 years (range 8-76), M: F ratio 48:54. The most common subtypes seen in our study were leiomyosarcoma (18.6%), dedifferentiated liposarcoma (11%), osteosarcoma (11%), well-differentiated liposarcoma (7%), carcinosarcoma (6%), and rhabdomyosarcoma (6%). Ninety-five out of 102 patients (93%) had at least one genomic alteration identified with a mean of six mutations per patient. Of the 95 biopsy samples with identifiable genomic alterations, the most commonly affected genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%). Notable co-segregating amplifications included MDM2-CDK4 and FRS2-FGF. Sixteen percent of patients received targeted therapy based on CGP of which 50% had at least stable disease.

Conclusions: Incorporating CGP into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease, as well as personalized matching of patients to targeted therapies such as those available in basket clinical trials.


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