title: Cancer Therapy Directed by Comprehensive Genomic Profiling: A Single Center Study.
abstract: Innovative molecular diagnostics deployed in the clinic enable new ways to stratify patients into appropriate treatment regimens. These approaches may resolve a major challenge for early-phase clinical trials, which is to recruit patients who, while having failed previous treatments, may nevertheless respond to molecularly targeted drugs. We report the findings of a prospective, single-center study conducted in patients with diverse refractory cancers who underwent comprehensive genomic profiling (CGP; next-generation sequencing, 236 genes). Of the 500 patients enrolled, 188 (37.6%) received either matched (N = 122/188, 65%) or unmatched therapy (N = 66/188, 35%). The most common reasons that patients were not evaluable for treatment included insufficient tissue, death, or hospice transfer. The median number of molecular alterations per patient was five (range, 1-14); median number of prior therapies, four. The most common diagnoses were ovarian cancer (18%), breast cancer (16%), sarcoma (13%), and renal cancer (7%). Of the 339 successfully profiled patients, 317 (93.5%) had at least one potentially actionable alteration. By calculating matching scores, based on the number of drug matches and genomic aberrations per patient, we found that high scores were independently associated with a greater frequency of stable disease ≥6 months/partial/complete remission [22% (high scores) vs. 9% (low scores), P = 0.024], longer time-to-treatment failure [hazard ratio (HR) = 0.52; 95% confidence interval (CI) = 0.36-0.74; P = 0.0003], and survival (HR = 0.65; 95% CI = 0.43-1.0; P = 0.05). Collectively, this study offers a clinical proof of concept for the utility of CGP in assigning therapy to patients with refractory malignancies, especially in those patients with multiple genomic aberrations for whom combination therapies could be implemented. Cancer Res; 76(13); 3690-701. ©2016 AACR.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bettzy
authors.initials: B
authors.lastname: Stephen
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daniel
authors.initials: D
authors.lastname: Karp
authors.affiliation: Sarah Cannon Research Institute at HealthONE, Drug Development, Denver, Colorado.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roosevelt
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Danxia
authors.initials: D
authors.lastname: Ke
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Center for Personalized Cancer Therapy, Moores Cancer Center, The University of California San Diego, La Jolla, California. rkurzrock@ucsd.edu.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D057285:Precision Medicine; D011379:Prognosis; D011446:Prospective Studies; D015398:Signal Transduction; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor